PT99445B - PROCESS FOR THE PREPARATION OF MONO-N-SUBSTITUTED 1,4,7,10-TETRAAZACYCLODODEAN DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

Tetraazacyclododecane compounds of general formula I <IMAGE> (I) in which E and Q are defined herein and their salts with inorganic and/or organic bases, amino acids or amino acid amides are valuable pharmaceutical agents.

Description

Description concerning the SCHERINS ΑΚΤ1ENGESELLSCHSFT, German, industrial s commercial patent, with headquarters in Berlin and Bergkamsn (postal address 170 -: 178 Miil lerstrasse, Berlin êS), German Federal Republic, (inventors? Dr. Johannes Platzsk, Dr Heinz Sries, Dr. Hanns-Joachi m Weinmann, Wol f-Riidiger Press and Dr. Hubert Vogler, residing in the Federal Republic of Germany) for PROCESS FOR THE PREPARATION OF

DERIVATIVES OF 1 , , 4,7,10- -TETRAAZACICLODODECANQ MONG-N-

- REPLACED

DESCRIPTION

The present invention relates to the objectives defined in the claims, ie, new mono-N-substituted 1,4,7,10-tetraaza-cyclododecane derivatives, their complexes and complex salts, pharmaceutical compositions containing these compounds, their use in diagnosis, as well as a process for the preparation of these compounds and pharmaceutical compositions.

In the early 1950s, metal complexes were considered as a means of contrast for radiology. The compounds then used were, however, so toxic that their application to human sar could not be considered. So it was very surprising that • certain complex salts turned out to be sufficiently

F.P i

its high efficacy, especially if tolerable can be administered, so that its application can be considered for diagnostic purposes in humans. As the first representatives of this class of compounds, the Gd DTPA dimeglumine salt (gadolinium complex 111 of dietiI-lenotriamino-pentaacetic acid) described in the European patent with the number of publication 715Ó4, and the meglumine comes out. of the GD DOTA (gadolinium 111 complex of 1,4,7,10-tetracarbox i meti-1, 4,7,10-tetraazo-cy clodecane) described in French patent 2,539,996. They were registered under the designations Magnevist ^<KS and Dotarem '*'.

An essential reason for its good applicability in the clinic lies in the t omog ry affi rence by r essonanc1 to n uc1ear, many brain tumors. Thus, at much lower doses of 0.1 mmol / kg of body weight than, for example, radiological contrast media in many radiographic examinations.

However, there was a desire to apply chelates also in higher doses. this is the case in particular for the detection of certain diseases outside the central nervous system with the aid of nuclear resonance tomography (diagnosis by NMR), especially when using chelates as means of radiological contrast. In order to keep the body's volume overload as low as possible, it is necessary to use highly concentrated chelate solutions. The chelates known so far are hardly suitable for this purpose, mainly due to their high osmolality.

Thus, there is a need for chelates that have a lower osmolality than the known chelates. At the same time, however, the requirements for the application of these compounds in humans must be met, with regard to the distance between the effective dose and the toxic dose in the animal test (the therapeutic spectrum), the specificity stability, the enhancement effect of the contrast, the tolerance, as well as the solubility of the

c α m ρ α ΐ »t ο · = · ~ ο ιτι ρ 1 and χ α s»

Thus, the present invention aims to present these compounds, as well as compositions that contain them, and yet to create as simple a process as possible for their preparation. These objectives are achieved by the present invention.

The complex compounds referred to in the present invention and the solutions prepared with them, surprisingly satisfy the aforementioned requirements »They have a reduced osmolality, as well as a therapeutic spectrum and / or a stability and storage capacity of the chemical components of the solution and / or an organic specificity and / or tolerance <p „e» less side effects here.-vascular or allergic type) as well as above all a contrast-enhancing effect more advantageous than the diagnostic methods used so far »

As proof of the exceptional and surprising properties mentioned above of the compounds to which the present invention refers, attention is drawn to Tablei at the end of the Experimental Part, in which the usual 1 / T ± (in plasma) relaxivities are compared as a measure the contrast enhancing effect of NMR contrast media, as an example based on some selected complexes to which the present invention refers »The Table reveals a notorious super: i. ority of these compounds in relation to the Magnevist ^<FS > and Dotarem ^<R> diagnostic means which are considered as current technological state »

Surprisingly, that of the complexes to which the present invention refers has a pharmacokinetic behavior different from Magnevist ^<R> and ρ odemsef maior parts

Provide ^<R> 3 after intravenous injection.

the Magnevist ^<F

They are distributed extraclularly, they are of glomerular secretion »kidney, through

There is practically no intact cell passage and extra-renal elimination »

It has been found that most of the compounds to which the present invention relates have separate membranes

surprisingly, both renal elimination and excretion in the faeces after parenteral administration. Surprisingly, elimination via the gallbladder is not the only extra-renal elimination route 5 in NMR assays in the rat, after intravenous administration of the compounds to which the present invention refers, surprisingly also has a potential: i. the contrast of the gastro-intestinal tract, ie, these compounds are suitable both for the diagnosis by specific NMR of organs of the hepato-bi1iar system, as well as of the stomach »The kidneys, as well as implanted tumors, are also contrasted»

Secretion through the stomach has the advantage of allowing a delimitation of the abdominal structures (eg, pancreas) of the gastro-intestinal tract, with simultaneous enhancement of the contrast of pathological processes (tumors, inflammation) »In addition, a representation of the renal system, the b can also be obtained from the gallbladder and gallbladder, as well as from lymph nodes »In addition to the improved representation of gastric ulcers and carcinomas, a control of the secretion of gastric juices can also be performed with the aid of radialogic processes»

Sur ρ reendent em e t e, at 3. g the complex compounds to which the present invention refers are also reabsorbed after oral administration, and then eliminated via the hepatic-bile route, i.e. they are also suitable as oral hepatic contrast media.

Through the use of the aforementioned compounds, it is also possible to help - and in addition to the diagnosis of the hepato-bi1iar system - both renal insufficient patients and patients suffering from gastro-intestinal disorders (at least 10% of the population in western industrialized countries) ) »Most of these patients, as well as a large number of patients in whom these diseases are suspected, have to undergo diagnostic tests» At the moment, two methods are used for gastro-intestinal diseases endoscopy and radiological diagnosis with the aid of barium-based contrast media »

These tests have several disadvantages: they are associated with the risk of radiation overload causing trauma, and they are associated with discomfort and possibly even risk for patients, and can therefore cause psychological stress »Most cases performed repeatedly , a hundred laer comp1exes to perform, are actively requiring the patient's active collaboration (eg taking a certain body position 5, and often cannot be performed on fragile and laughing patients). present and location of presenting these the use of

Thus, new diagnostic methods for detecting gastro-intestinal diseases, which are not disadvantages, are also achieved with compounds and means of diagnosis.

Even without specific measures, its pharmacokinetics allow an improvement in the diagnosis of numerous diseases. The complexes are mostly eliminated without alteration, and relatively quickly, because especially in the case of the use of relatively toxic metal ions, no harmful effects are observed, even with high doses.

The practical use of the new complexes is also facilitated thanks to their good chemical stability.

Another important advantage of the complexes and complexing agents described is their extreme chemical versatility. In addition to the central atom, it is possible, through the selection of several substituents in the macrocycle and / or the salt forming agents, to adapt their properties to the requirements of efficiency, pharmacokinetic, tolerance, solubility, ease of handling, etc. ». Thus, it is possible, for example, to achieve a very desirable specificity of compounds for diagnosis and therapy in relation to body structures, biochemical substances, metabolic processes, tissues or organic liquids.

d eterm i nad as and the state

The macrocyclic compounds to which the present invention relates are characterized by the general formula wool

Y “ z Y / x— _THE,

(I) in which

E represents a -CH (R ¹ ) -CO ^ Y radical with Y ~ a hydrogen atom and / or a metal ion equivalent of an element with the order numbers 21-29, 31, 32, 37-39, 42 -44, 47, 49 or 57--83, and R ¹ = a hydrogen atom, a C 1 -C ₃ alkyl group optionally substituted with 1 to 6 straight or branched chain hydroxy groups, an C aryl group _is -Ci _O or ar — alkyl with Ct-Csoíí

Q represents a -CH (R ·) -CH (OH) R radical, with R = a straight or branched chain C 1 -C 6 alkyl group, or ar-C 1 -C alkyl. _3O , containing 1 to 10 oxygen atoms are optionally substituted with 1 to 6 hydroxy or OCOR® groups, but R ^s represents a hydrogen atom or a C ±-C ₃ alkyl radical, straight or branched, aryl with C ^ -Cxo or ar-alkyl with CfC _S o, which may possibly have 1 to 2 -OCO groups, 1 to 2 cyclohexane and / or cyclohexyl radicals (which in turn can be replaced with 1 to 3 groups (CH _S ) _K COGR® where K - 0-10), possibly 1 to 5 alkoxy groups with C _a , .....

-Cr, aryloxy with C & ..... C _1O or aralkoxy with C _r -Ci _O , possibly a radical -NR ^ -COR® or -C0NR2R ³ , sm that R- * have the definitions given for R ^s , and / or 1 to 2 CQ radicals _s R®se whose aryl radicals possibly present in the chain can be replaced with 1 to 3 alkyl radicals with Cx-C: _3Q straight or branched chain, aryl with C ₆ -Cio or air-conditioning with Cr-C®o ₃ * · '

possibly having 1 to 5 oxygen atoms, 1 to 3 hydroxy groups, 1 to 5 alkoxy groups with C 1 -C ₇ and / or 1 to 3 CCH _S ) _K COOR ³ ? groups, or 1 to 3 F radicals, Cl, Br, -OH, NO ^ -, NHa-, NCS, COSR ^S , NHCOCH ^ Cl-, NHCOCH ^ Br-, NHCOCHsRs- ~ js

R ^? represents a hydrogen atom or R, s in the case of R ^? represent a hydrogen atom and be in the presence of a C2 -Cso 2-oxa-alkyl chain, this must be replaced with at least one of the radicals described above, in addition to a terminally present mstoxy or stoxy group ?;

or represents a second tetraazacyclododecane molecule linked via a bisC (hydroxy) -alkylene chain — CHja — CH-K-CH-CHs ”- where! <represents a cobalt (II) alkylene (II), neodymium (III) chain,

OH OH with C ± -C _xa> containing 1 to 6 oxygen atoms, possibly 1 to 2 tasnciloxy, phenylene groups, phenylenoxy s / or phenylenedioxy, and substituted sventualments with 1 to 6 hydroxy groups, í a & hydroxy groups • • C ₃ -C & alkyl and / or ia 8 alkoxy groups with 0 ₃ . - 0 ··, · = · or ar-al c ó xi = as well as their salts with inorganic and / or organic bases, amino acids or amino acid amides »

The compounds of general formula 1 with Y representing hydrogen are called complexing agents, s with at least two of the Y substituents representing one equivalent of metal ion are called metal complexes »If the pharmaceutical composition referred to in the present invention is intended for diagnosis of NMR, the central ion of the complex salt must be paramagnetic »This is especially the case of bi- and trivaient ions with order numbers 21-29, 42, 44, and 38-70, = suitable ions are example chromium (III), manganese ϊI>, ferroCII), nickel (II), copper (II), praseodymium (II), samarium (II) and ytsrbiumCIXX) »Due to their very strong magnetic moment, gadolinium (II) ions are particularly preferred, terbioCIII), dysprosium (III), holmioCXII), erbium (III) and iron (III).

For the use of the pharmaceutical compositions referred to in the present invention in nuclear medicine, the central atom must be radioactive. For example, radioisotopes of the elements copper, cobalt, gallium, germanium, itrium, strontium, tecnetium, indium, yterbium, gadolinium, samarium, silver, gold, rhenium and iridium are suitable.

In the event that the pharmaceutical compositions to which the present invention refers are intended for use in radiological diagnosis, the central ion must be derived from an element with a higher order number in order to obtain sufficient absorption of the RX. It has been found that diagnostic means containing a physiologically tolerable complex salt with central element iSes with order numbers between 21-29, 42, 44 and 57-83 are suitable for this purpose; these are, for example, the lanthanum ion <11> and the aforementioned ions in the lanthanide series.

The alkyl, aryl and / or ar-alkyl radicals possibly present for R ³ · and or possibly present in R as substituents for an aryl radical possibly present, respectively have 1-30, or 6-10, or 7- 30 carbon atoms, and can be straight or branched or unbranched, cyclic, saturated or unsaturated, containing in the case of R · 'possibly 1-6, preferably 1-3 hydroxy groups, in the case of R oxygen, 1-3 hydroxy radicals.

eventually 1-5 atoms of 1-5 preferably 1-3 groups

a.loxy i_om C _x —Cy and / or 1—3 groups »ICs ^ k C00R ³² with K

0-10, preferably 0-5.

As radicals, for example -CH », -C ^ Hs, -i, -C _B H _X r, Ci <£, H; 5rs · ι“ CirHsa, - CHaOH, - CH ^ CH ^ OH, —CH (UH) CH32UH preferred may

C l gHrjs 1, “bôHs n

-CH (OH) CH COH) CH ^ OH, ~ QCH- ₅ , -QC ^ Hs,

- □ CHssCHsaQCH®, -OCHaCHaOCHffiCHs.OH, - (CH ^) ®0Η,

- <CHS) _S CO _S H, -OCHsCOsH, -0 (CH _S ) «, ΟΟ ^ Η,

-CH-aCOai CsHv, -CHa-O-CH <CO _ffi H) -CH _to CO _s H,

-O-CH _S ~ CH (OCH-,) -CHs-OCH®.

R ³ · and R ^; preferably represent

-OCH ^ Ha, -CHaCCkH,

-CHsaCOsBCsaHsg, respectively an atom of

hydrogen"

R represents a radical], C 1 -C 6 alkyl; preferably straight or branched or unbranched chain.

saturated or unsaturated, or an air-alkyl radical with C7.-C.-30 which is interrupted with 1-10, preferably 1-5 oxygen atoms, and is eventually substituted with 1-6, preferably 1-3 groups hydroxy or -OCOR®. It can have 1-2 cyclohexane and / or cyclohexylene radicals, which in turn can be substituted with 1-3, preferably a (CH _{; a} ) _K COOR® group.

In addition, the radical with Cx ~ -Dog at the position of R can be substituted preferably 1-3 alkoxy groups with CxCr, aryloxy with C4 -C10 or radical -NR ^ -COR »(as ps IMHCOC * H _S a radical • CONR ^ R® C with CONCHCàHe, CONCHrsCoHs, CONI-is, CONHC ^ Ht ·) and / or 1 to 2 CO _E R ~ - (as ps COaCH », CO ^ CsHs, COs» 'Pr, 1-3 , preferably one

COa.CHa.CoHs>

NCHtsCOCHts

with 1 _ = ·, HI J in with Co ” ¹ - · 10 or ! -iw · '‘55 7 OC * H _S , one NHCOCa-S ‘55 π C0NHC1 k? 5

radicals COeCBu.C>, eventuaimente aryl moiety present in this chain can be substituted with alkyl with C _{to O,} preferably 1-2 COasR®, NHCOCH- Cl-C -.,

1 to 3, from p reference 1-2 of radi «. there, there aryl and / or ar-alcqui10, and / or with 1-3, F radicals, Cl, Br, -OH, NOa-, NHa-, NCS, NHCOCHasBr-, NHCOCHaR ⁵³ -, CON '.

As preferred R radicals can be referred to

-CHía-O-CoHs, -CHar-O-CHsCoHe, -CH _to -O ~ C 1 oH _EO 0H,

-Cha the H-O-Cx _{of <:} "COOH, -CH _O" C _and Hχ _<: -COOH, -CH _are CH _ffl - CC ^ Hχ> -OCHr,.

-CHat-CHa-CHa.-CHa.-O-CHat-COOH, -Ci-bO-CoHxc, -COaH, “CHas-O-CoH 1 _o -OH, -C _and Hχ _E -O-CH _E ~ COOH , -CH _K -OC _S Hχ oNHCOCoHs, -CHa-O-CatHsNHCQCoHs, -CH-QC ^ HsCCNH-CsH-r, -CHS-0-CH2CH2-0-CHSCHS-0-CSH! Χ, -CH _S “O -CH _S ~ CH <OH) CH ^ OH, CHa-O-CoHzvMCS, -CH ₃ -0-CoHz, .0CH.-3, -CHa-O-CHaCHaCHsCôH ^ OCH », -CHa-O-CotU-Cl , -CH _s O-Co'rU.-CsHxo-OH, -CHa-QC ^ H »(CH»> 2, -CHa-O-CoHz ,. (CHa »> _S. -COOH, ~ CH2-O- CJU. ~ OCHa.COOH, -CHa-OC J-UCOOH, -CHaO-CHa-Col-UCOOH, -CHsO-CoH ^ CH ^ COOH, ~ CH _to O ~ C _& .H.xCH _s COaC _s Hs,

CCHai ^ -O-CHa-CoH

Cl-b-OCO-Cχ _b H ₃ χ, - í CH _S > ^ -OCH »,

-CHat-OC ^ Hχ «-O-CHsCoHb, -CH _S -O“ C ^ H _x «OH

ΌωΗχ _ώ - (CH-O-CH _S -C _& H _S ) -C _to H _s , -C ^ H χ ^ -QC ^ H ^ -O-CH ^ -C ^ Hs,

-C ^ Hχ θ-Ο-Ο ^ Ηζ ,, - ΟΗ, (CH®) «y-O-CHa-CJ ^ -CH ^ COOH,

- <CH ₂ ) _and? --OC x © Heo-OH, - (CHffi) -O-CsHχ © -CQOH, (CH _S ) ^ -OCOCH, _S ,

- <CH _a ) ς, -O-COCxxH ^, - (CH _a ) ς, -OCOCaH ^ COOH, - (CH- _a ) -OCOC _and H _fl .COOH,

- <CH _a ).

of the present invention of the general formula I in the ethanol

i) -alki1eno ohi gé ni ο ρ r esent es

DuS {... umpOstOs • are dimers, ie compounds in which Q represents a second molecule linked via a bis chain (G-hydroxide -CH _S “-CH ~ K-CH” CHa “» 0 number of atoms

OH OH in the K alkylene chain with 0χ-0 &, preferably with Οχ-Cx ©, is preferably 1-3. This optionally has 1-6 hydroxy groups and / or 1-6 hydroxy-alkyl groups with C1-C * and / or 1-8, preferably 1-2 alkoxy groups with Cf-C _T , aryloxy and / or air-alkoxy „

As preferred alkylene chains 1 <may be mentioned for example

-CHa-O-CHa-, ΟΗ ^ Ο-ΟΗ ^ Η ^ -Ο-ΟΗ ^ -, -ΟΗ ^ -Ο-Ό ^ Ηλ-Ο-ΟΗ ^ -,

-CHs-0-Cz..He-O-CHs-, -CH ^ O-CH (CH ₃ OH) -CH _S -CH C CH _S OH) -O-CH _S -,

-CH _s a-CHs-CH C OH) -ΟΗ ^ -Ο-ΟΗ _ξ -, -CH _S -Q-CH _S -CH (OCH »5 CH _a -O-CH _s -,

-CHs-aCHs-C (CH ^ OH) e-CHs-O-CH ^ -, -CH _S ~ OC J ^ -Q-CHis-,

-CHs-O-CHs-C ^ H ^ -Cha-O-CH -, - CH? -O-CH? -CH (OH) -CH COH) _t2 -CH -O-CH _a -, -CHs O -Cha CS-C ~ CH BOH) -CH -O-CH _{S S} - "CH _O" C _<-OC ^ H _{& 4i> l} Hz.-O-CHs'

The remaining acidic hydrogen atoms, that is, those that have not been replaced by the central ion, may be eventually substituted in whole or in part by cations of organic and / or inorganic bases, amino acids or amino acid amides.

Cations, for example, organic lithium, magnesium and especially sodium ions are, among others, secondary and tertiary ions, as suitable inorganic ρ are potassium, calcium, suitable cations of arnium bases in primary materials. ,

and. ethanol-amine, diethanol10

-amine, morpholine, glucamine, Ν, Ν-dimethyl-glucamine and in particular N-methyl-glucamine. Suitable amino acid cations are those of lysine, arginine and ornithine, as well as amides are e.g. other acidic or neutral methylamides, e.g. glycine-ethalamide and serine-methylamide.

tetraazaeiel. odecane of the formulation · general preparation

1i nacanposios refers to the present invention, it is carried out by reacting compounds of general formula II in a known manner

(II) which in which

E ^z represents the radical indicated for E, in the hydroxy groups there are possibly protected, an educate of the general formula III or IV eventuals with

(ΙΠ),

K ¹

(IV).

in which

K 'represents the radicals indicated for K, in which any hydroxy groups are eventually protected,. R® _and ri =>t'ê'm definitions indicated for R ^z and R, but do not contain

any groups NH _S , NCS, NHCOCH ^ Cl or NHCOCH ^ Br, and in which eventual carboxyl groups are eventually protected, in water or in water miscible solvents, such as pe

acetonitrile, DMF, DMA, ethanol, methanol, dioxane.

THF, DMSO,

DME or mixtures thereof, at temperatures of 0 ° -170 ° C, preferably at 20 ° “100 ° C, for 12 to 48 hours, preferably for 12 to 24 hours, adding inorganic and / or organic bases such as PE hydroxide potassium, sodium, lithium, calcium, barium, magnesium, butylamine, pyridine, DMAP,

Reillex < ^R >

l gf / con The removal of protection still present, groups the agents in tazer eagιr r thus obtained complexing Cy represents hydrogen ^'1 part at least one metal oxide or metal salt of an element with order numbers 21-29 , 31, 32, 37-39, 42-44, 47, 49 or

57-83, and then - if desired - the acidic hydrogen atoms present are replaced by cations of organic and / or inorganic bases, amino acids or amino acid amides, breaking, if the desired final compounds are to be

NCS contain NH _ffi groups, educts of the general formula have N0 groups _{; a} · - qu CO- _a R these last groups

NHCOCH ^ Cl de

NHCOCHs.Br or CON _{: s} ,

III that instead of these groups ~ ^B -, and then transforming into the above mentioned and desired functional groups, this transition can be carried out before or after the complexing of the complexing agents and subsequent replacement of the acidic hydrogen atoms still present with the metal ions respectively desired.

As protecting groups for hydroxy groups can be considered all those that can be easily introduced and later also easily eliminated with the recovery of the desired free hydroxy group. Preferred protecting groups are ethereal groups, such as benzyl, 4-methoxy-benzyl, 4-nitro-benzyl, trityl, diphenylmethyl, triphenyl-methyl, trimethyl-methyl, dirnetyl-butyl and difeni 1 — t-buti Isi 1 i lo. However, the hydroxy groups are preferably protected in the form of acetals, with e.g., acetone, acetaldehyde, cyclohexanone or benzaldehyde

The hydroxy protecting groups can be eliminated by the known processes, eg in the case of benzyl ether through reductive fission with lithium / ammonia, or hydrogenolytic fission in the presence of palladium / carbon, and in the case of fission of an ether or acetal by treatment with acid with the aid of cation exchange resins, trifluoroacetic acid or mineral acids (see eg Protective Sroups in Organic Synthesis, T. W Sreene, John Wiley and Sons, (1981)).

As acid protecting groups can be considered lower alkyl, aryl, or ar-alkyl groups, eg methyl, ethyl, propyl, n-butyl, t-butyl, -phenyl, benzyl, diphenyl-methyl, tri -phenyl-methyl, bis-β-nitro-phenyl) -methyl, as well as trialkyl-silicyl groups.

The elimination of two acid-protecting groups is carried out by processes known to those skilled in the art, for example through hydrolysis, hydrogenolysis, alkali saponification of esters with alkalis in aqueous-alcoholic solution at temperatures of 0-50'- ' C, acetic saponification with mineral acids, or in the case of pe »t-faulilic esters, with the aid of tri-fluoro-acetic acids»

For the trans-manufacture of the tri-substituted tetraazaocyclodecane IX derivatives known by European Patents EP 255 471 and Ep 287 465, with epoxides III, an excess of compound III of 1.05 to 5 times is used, preferably 1 , 05 to 3 times »

On the contrary, in the synthesis of macroc i c1 the d i mers are reacted with 0.1 to

0.49 equates to compound IV.

The complexing agents thus obtained are isolated after purification on silica gel columns, reverse-phase columns (RP-18) or ion exchange resin columns (IRA 67, IR 120, AMB 252).

The functional groups NH _S , MHCOCHaCl, NHCOCH-aBr and NOS possibly desired in the final compound are generated after alkylation with an epoxide III containing a NO group (before or after the possibly desired introduction of the

metal in the macrocyclic compound), according to methods known from the literature (European Patent publication N5.292 689p Patent Med »Chem»

US 4,678,6673 Bioconjugate Chem »1990, 1

1989, 32

The epoxides 111 and IV required as educts are known or can be prepared in analogy with processes known from the literature, transformation of alcohols with epichlorohydrin

p.e »through (Synt hesis 1983,

117p Houben-Weyl, Methoden der Organischen Chemie, Vol. »613, Seorg-Thieme Verlag Stuttgart, 19655 and epoxidation of ally ™ -substituted alcohols or unsaturated ethers CJ» Org »Chem» 35, 215 Cl9705, Houben-Weyl, Seorg- Thieme Verlag Stuttgart, 19453 Tetrahedron-Lett ,, 1965, 8495 The preparation of the metal compounds to which the present invention relates is carried out as described in German Patent 34 01 052, by dissolving or suspending the metal oxide or a typical metal salt. and. nitrate, acetate.

carbonate,: loride or sulfate of an element with order numbers 21-29, 31 ~ p-rn

42-44, 49,

57-835 in water and / or in a short-chain alcohol (such as methanol, ethanol or isopropanol) and reacted with -the solution or suspension of the equivalent amount of the complexing binder, and then, if desired, the atoms are still replaced of hydrogen acids present by cations of organic and / or inorganic bases or of amino acids of the ft. introduction of the desired metal ions can be carried out both before and after the elimination of the protecting groups of the hydroxy groups. ft neutralization of free carboxyl groups present is made with the aid of inorganic bases Cp »and» sodium, potassium, lithium, magnesium or calcium and / or organic bases such as, among others, amine?

primary, secondary and tertiary, such as p »e» morpholine, g1ucamine, N-mst i1-g1ucamine, and g1ucamine, as well as ethanol-amine, Ν, N-dimethylarginine and ornithine.

as basic amino acids, such as e.g. lysine, or amides from originally neutral amino acids or acids.

To prepare the complex neutral compounds, it can be added to the acid complex salts in aqueous solution or suspension, both of the desired base, until the neutral point is reached. The solution obtained can then be evaporated to dryness in a vacuum. »It is often advantageous to precipitate neutral-formed salts by adding water-miscible solvents, such as, short-chain alcohols (methanol, ethanol, isopropanol and others), short-chain ketones (acetone and others), polar ethers ( tetrahydro-furan, dioxane, 1,2-dimethoxy-ethane and others), thus obtaining crystal isolates that are easy to isolate and to purify »As spatially advantageous, the addition of the desired base to the reaction mixture was revealed immediately during the formation of the complex, thus saving one step in the process »

One or three possibilities for obtaining neutral complex compounds is to transform all or part of the acid groups remaining in the complex, for example esters or amides. This can be done by further reacting the ready-made complex Cp and e by saturating transformation of free carboxyl groups with dimethyl sulfate »

The preparation of the pharmaceutical compositions to which the present invention refers is also carried out by the processes themselves already known, suspending or dissolving the complex compounds of the present invention in an aqueous medium - possibly adding the usual additives in galenic and eventually sterilizing the solution or • suspension »Physiologically tolerable additives suitable Cp» e »form or dec decompex (C p» e »psntaacetic) or - if necessary are pe» tr-omethamine buffers), acidic di-ethylene agents tri ami noelectrolytes as pe

sodium chloride, or ascorbic acid.

if necessary mt i-ox i d before p.e.

If they are desirable for enteral administration or other purposes, solutions or suspensions of the compositions referred to in the present invention in water or physiological saline, they are mixed with one or

Í5

more of the usual adjuvants in galenic íp «e» methyl 1-cellulose, lactose, mannitol) and / or surfactants (eg lectins, Tween, Myrj ^<R> ) and / or flavoring agents for flavor recovery (eg essential oils ).

In principle, it is also possible to prepare the pharmaceutical compositions to which the present invention relates without isolating the complex salts. In any case, care must be taken in the formation of chelates, so that the salts and saline solutions of the present invention are practically free of non-complexed metal ions, which can be toxic.

This can be ensured e.g. with the help of colored indicators such as xylenol orange, through control titrations during the preparation process. Thus, the present invention also relates to a process for the preparation of complex compounds and their salts. As a form of ultimate safety, purification of the complex salt is left.

The pharmaceutical compositions to which the present invention refers preferably contain 0.1 pMol 3 Mol / 1 of complex salt, and are generally dosed in amounts of 0.1 pMol - 5 mkiol / kg. They are intended for parenteral and enteric application. The complex compounds referred to in the present invention are u.ti 1 i. z ad os s

1. for MRI and RX diagnostics, in the form of their complexes with elements ions with the order numbers 01 Δ9 .ÍLil ca «sz — ew c— .L a» f η ig »F w · ..» * 5 Ww t;

2. for radio-diagnosis and radio-therapy, in the form of their complexes with the radioisotopes of the elements with order numbers 21, 26, 27, 29, 31, 32, 37-39, 43, 47,

49, 62—64, 67, 70, 71, 75, 77, 79 and 83.

A s c o m ρ o s ions and f a r m a c e u t i c a c e s referred to in the present invention satisfy the numerous requirements to be used as a contrast medium for nuclear resonance tomography. Thus, they are exceptionally suitable for, after oral or parenteral administration, to improve • by increasing the intensity of the signal, the

expression of the image obtained with the aid of a nuclear resonance tomograph »In addition, they have the high efficiency necessary to overload the organism with the minimum possible amounts of foreign compounds, tolerance necessary to maintain the non-ex ames character.

The good and good invasiveness of water solubility and refers to reduced osmolality of the compositions to which the present invention allows the preparation of highly concentrated solutions, in order to keep the volume overload of the circulatory system within reasonable limits, and to compensate for the dilution by body fluids, ie », the diagnostic means for NMR must be 100 to 1000 times more easily soluble in water than for NMR spectroscopy» In addition, the compositions referred to in the present not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or exchange of ions that are not covalently bound in the complexes - and in themselves toxic - during the period of time that the new ones contrast media are new and 1 im: i. n ad os is only done extremely slowly

In general, the compositions referred to in the present invention are dosed for use as diagnostic means for NMR, in amounts of 0.0001 - 3 mMol / kg, preferably 0.005-0.5 mMol / kg. Details of use are discussed eg in H »J» Weinmann et al =, Am »□» of Roentgenolagy 145, 619 (1984).

In addition, the complex compounds referred to in the present invention can be used advantageously as susceptibility reagents and as shift reagents for in vivo NMR spectroscopy »

The compositions to which the present invention refers are also suitable as means of radiodiagnosis, thanks to their favorable radioactive properties and the good stability of the complex compounds contained therein. »Details on their application and dosages are described, eg,» in Radiotracers for Medicai Apl1ications,

CRC-Press, Boca. Raton, Florida.

Another method of visualizing radioisotope images is positron emission tomography, which uses positron emitting isotopes, such as pe ⁴ :! ⁵ Sc, ** Sc, ^ss Fe, ® «Co e * ^s Ga ( Heiss, WD? Phelps, M.Esp Positron Emission Tomography of Brain, Springer erlag Ber1i η, Hei delberg, New York, 1983).

The compounds to which the present invention refers can also be used in radio-immunological or radiation therapy. This is distinguished from diagnostic methods only by the amount and type of isotope used. Its aim lies in the destruction of tumor cells through short wave radiation, rich in energy, and with as little range as possible. I3 ions ~

- suitable transmitters are e.g.

Suitable emitting ibes, reduced, are preferable to ^Ώ1κ Βί »

4sq _f ^s Ga with times of suitable ³ ®8d,,, '......, Bi e,

A fact-emitting and ^r -'Ga and semi-ion ion gives off xsn-Gd electrons because it can be obtained from neutron capture medium.

If the pharmaceutical composition to which the present invention refers is intended to be used in the variant proposed by R.L. Mills et al. CIMature Vol. 336,

C1988) pág.7873 for therapy for radiation, the central ion must be derived from an isotope of MoSbauer as p. · ^S7 'I Fe or ^1531.

In pharmaceutical applications to which it is intended to be administered together in vivo application of the compositions of the present invention, these can with a suitable ex dpi, as

e.g. serum or physiological saline, and in conjunction with another protein, such as e.g. human serum albumin. The dosage depends on the type of cell disorder, the metal ion used and the type of the method, e.g. brachy — therapeutic.

The pharmaceutical compositions to which the present invention refers are applied parenterally.

Details of the application of means

radio-therapeutics are discussed e.g. in R.W.Kozak et al., TIBTEC, October 1986, 262.

The pharmaceutical compositions to which the present invention refers are exceptionally indicated as contrast media for radiology, in particular it should be noted that with them the known anaphylactic reactions of iodine-containing contrast media are not observed in biochemical-pharmacological examinations » They are especially useful because of the advantageous absorption properties in the higher stress zones of the tube for digital substrate techniques »

In general, the pharmaceutical fields referred to in the present invention are dosed for use as a radiological contrast medium, in analogy with, for example, meglumin-diatrizoate, in quantities of 0. 1.5 ml ^v / kg , preferably 0.25-1 mMol / kg »

Details on the use of radiological diagnostics are discussed by »in Barke, Roentgenkontrastmittel, G» Tjieme, Leipsig (1970) and P. Thurrn, E »Bíicheler - Einfuhrung in die Roentgendiagnosti k, G.Thieme, Stuttgart, New York ¢ 1977 ).

In globalization, new complexing agents, metal complexes and metal complex salts have been synthesized, opening new possibilities in diagnostic and therapeutic medicine. Above all, the development of new imaging processes in the field of medical diagnosis makes this development desirable.

The following examples are intended to better illustrate the objects of the present invention »

EXAMPLE 1

a) 1,1 '- (2,9-Dihydroxy-4,7-dioxa-l, 10-decyl) -bis - [(4,7,10-tris-carbaximethyl) -l, 4,7,10- tetraazacyclododecane

Dissolve 17.9 g (51.67 mmol) of 1,4,7-tricarboxymethyl1-1,4,7,10-tetraazacyclododecane CD03A) in SO ml of water and adjust to pH 13 with NaOH. 5N. Then add a solution of 3 g (17.22 mmol) of

1,2-9,10-diepoxy-4,7 “dioxadecane in 30 ml of dioxane, and shake

for 24 hours at 30 * C. Adjust the solution to pH 2 with 10% HCl and evaporate in vacuo. Dissolve the residue in a little water and purify it on an ion exchange resin column (King 1 lex = poly- (4, -vinylpyridine); elute with water). Evaporate the main fractions in a vacuum and purify the residue by chromatography on RP-1S (LiChroPrep / tetrahydro-furan / methanol / water gradient eluents) „After evaporating the main fractions, 3.82 g (39% of the value) theoretical) of an amorphous compound.

Analysis (for anhydrous compound):

049.87 H7.67 N12.92 calculated

C49.80 H7.81 NI2.83

b) Bis-gadolinium complex of 1 _f 1 '- (2,9-dihydroxy-4,7-dioxa1 _r 10-deeyl) -bis- [4,7,10-triscarboxymethyl 1) -1,4,7, IO-tetraasacyclododecane

Dissolve 5 g ¢ 5.77 ¹ mmol) of the compound of example la) in 40 ml of deionized water and add 2.09 g (5.77 mmol) of gadolinium oxide. have 3 hours at 90 ° C. Stir the cooled solution for 1 hour at room temperature with 2 ml of alkaline ion exchange resin (IRA 410), respectively. Filter the resins and boil the filtrate with active charcoal. After filtration and lyophilization, 58 g (97% of theoretical value) of an amorphous powder are obtained.

Analysis (referring to the anhydrous compound):

036.79 H3.14 N9.53 Sd26.76 calculated

C46.7 H5.21 N9.46 8d26.71

EXAMPLE 2

â) 1,1 ’- (2,6-Dihydroxy-4-oxa-1,7-hepti1) -bis - [(4,7,10-triscarboxymethyl) -1,4,7,10-tetraazacyclododecane

In analogy to example la) 1,2-o, 7-diepoxy-4-oxa-heptane was used instead of 1,2-9,10d i ep ô xi -4,7-di ox ad ec an .

Yield: 32% of the theoretical value of a radio component.

Analysis (for anhydrous compound)

C49.63 H7.59 M13.62 c a1c u1 ad o C49 ₅ 58 H7.65 NI 3.54

b) Bis-gadolinium complex of 1 _f 1 '- (2,6-dihydroxy-4-oxa-1 _r 7 -heptyl) -bis- [4,7,10-triscarboxymetll) -1,4,7,10 -tetraazacyclo-

dodecane In analogy with example 1b) used for complexing the title compound of the example 2a) in place of the title compound of the example. Yields 96% of the theoretical value of

an inco1or, amorphous powder „

Analysis (referring to the anhydrous compound)?

836.10 H4.99 M9.90 Gd27.80 calculated C36.02 H5.07 N9.82 6d27.73 c) Bis-complex -yterbium of l, l '- (2,6-dihydroxy-4-oxa-1,7- -hepti1) -bis- [4,7,10- -triscarboxymethyl1) -1,4,7,10-tetraazacyclo- dodecane In analogy with example 1b)

yterbium oxide was used instead of gadolinium oxide.

a glazed compound. Yield? 97% of the theoretical value of

Analysis (referring to the anhydrous compound)?

C35.11 H4.85 N9.64 Yb29.76 calculated C35.03 H4.92 N9.57 Yb29.68

d) 1 _F 12,6-dihydroxy-4-oxa-1,7-heptyl) bis-[4,7,10-triscarboxymethyl) -1,4,7,10-tetraazacyclo-bis-dysprosium complex

dodecane In analogy with example 1b)

Dysprosium oxide was used instead of gadolinium oxide.

amorphous powder. Kendimsntos 98% of the theoretical value of

Analysis (referring to the anhydrous compound) s

C35.76 K4.94 N9.81 Dy28.46 calculated C35.66 H5.03 M9.74 Dy28.40 jC. X

e) 1,1 '- (2,6-dihydroxy-4-oxa-1,7-hepti1) -bis- [4,7,10-triscarboxymethyl) -1,4,7,10 bis-bismuth complex -tetraazacyclododecane

In analogy with example 1b) uti 1, bismuth oxide was used instead of gadolinium oxide.

Yield: 95% of the theoretical value of ρ ó amor f α, i nco 1 or „

Analysis (referring to the anhydrous compound):

C33.07 H4.57 N9.07 Bi33.85 calculated

C32.98 H4.63 N9.00 Bi 33.78

EXAMPLE 3

a) l, l '- (2, 11-Dihydroxy-4,9-dioxa-dodecyl) -bis - [(4,7,10-tris-carboxymethyl) -1,4,7,10-tetraazacyclododecane

In analogy with example la) 1,2-11,12-di ep o x i-4,9-d i ox a-dod ec an in 1ug ar d e

1,2-9,10-d i epoxy i-4,7-d iox adecane,

Yields 37% of the theoretical value of a colorless compound.

Analysis (referring to the anhydrous compound):

C51.00 H7.88 NI2.52 calculated

C49.93 H7.96 NI2.47

b) 1,1 '- {2,11-dihydroxy-4,9-dioxa-dodecyl) -bis- [4,7,10-triscarboxymethyl) -1,4,7,10-tetraasacyclododeean bis-gadolinium complex

In analogy with the example 1b) ut i1i turned to the complexation of the title r-compound of example 3a) in place of the title compound of example ia. 98% of the theoretical value in

an amorphous powder.

Analysis (referring to the anhydrous compound):

C37.92 H5.36 N9.31 Gd26.13 calculated

C37, S4 H5.41 N9.24 8d26.08

EXAMPLE 4

a) 10- (2-Hydroxy-11-bsn2yloxy-undecyl) -1,4,7-triscarboxymethyl1-1,4,7,10-tetraazaeiclododecane

Dissolve 28.73g (103.92 mmol) of

1,2-epoxy-11-benzyloxyundecane and 10 g (28.86 mmol) of 1,4,7-tricarboxymethyl 1-1,4,7,10-tetraazacyclododecane (= D03A) in a 50 ml dioxane / SOml mixture of water, and adjust to pH 10 with 6N KOH „Stir for 24 hours at 70-C. Evaporate to dryness, recover the residue with 200 ml of water / 50 ml of methanol and extract 2x with 100 ml of t-fouti1-methyl ether. Adjust the aqueous solution to pH 3 with 5N HCl and evaporate to dryness. Boil (extract) the residue with 200 ml of methanol / 80 ml of methylene chloride.

Cool in shower in q a I o e filter the chloride potassium precipitate. AND air vapor- o -ϊ i1 auger in a vacuum, to dissolve the residue in 45 ml ds water / 20 ml of ethane 1 and then .d.da leak about a

poly- (4-vini1pyridine) column. Elute the compound with a 1: 3 ethanol / water solution. After evaporating in vacuo, chromatograph the residue on a reverse phase column (RP 18 / eluent ~ water gradient / tetrahydro-furan). After evaporating the main fraction, 12.22 g (68% of theory) of a glassy, highly hygroscopic compound are obtained. Analysis (referring to the anhydrous compound):

C6 1.71 H8.74 N9, OO cal culated

Col, 82 H8.91 N8.87

b) Gadolinium complex of 10- (2-didroxy-11-benzyloxy-undeci1) -1,4,7, -tris-carboxymethyl 1-1,4,7, 10-tetraasacyclododeean mmol) and add 3 hours to with 3 ml of resin

Filter the

Dissolve 10.77 g (17, compound of example 4a) in 50 ml of deionized water 3.13 g (8.65 mmol) of gadolinium oxide. Heat to 90 ° C. Stir the cooled solution for 1 h acidic peremut resin (AMB 252c) and 3 ml slightly alkaline ion exchange (IRA 67). resins and lyophilize the filtrate.

Yields 13.17 g (98% of theoretical value) of an amorphous, colorless powder.

ftnálisis (referring to the anhydrous compound) s

C49.46 H6.62 N7.2i Gd20.24 calculated

049.23 H6.8Í M7.15 Gd20.13

c) Iron coiapleKO of 10- (2-didroxy-11-ben2yloxy-undecyl) -i, 4,7, -t. cis-carboxy methyl-1,4,7, 10-tetraasacielododecane used iron oxide

c.m sharpen og ia eom (II) instead of oxide

Yields 89% of gadolinium example 4b). theoretical value of a yellowish powder »

Analysis (referring to the anhydrous compound)?

C56.8S H7.6Í N8.29 Fe8.27 calculated

C5Ó, 69H7,52 NS, 34 FeS, 18

d) Manganese complex of 10- (2-didraxy-11-benzyloxy-undeci1) -1,4,7, -tris-carboxymethyl 1-1,4,7, 10-tetraasacyclododeean used or act on act of gadolinium »However acidic ion exchange hit the filtrate at 1 i of i 1 iz air»

In analogy with example 4b) manganese (2) instead of oxide, it is only stirred later with the resin (IR-120). After filtering the resin, pH 7.3 with 1N NaOH, then

Hte? Nd i ment of the theoretical value of «a glazed compound» Aná1i se (referring to

Η »η mywM] i ç · ~ 5 í

855.01

H7.44 anhydrous compound) § N8.03 Mn7.87 N8.17 Mn7.71

In the d, O t .. al cul ed

Na3.17

EXAMPLE 5

a) 1,2-Epoxy-l1-methoxy-undecane

Dissolve 9.35 g (51.3 mmol) -methoxy-undec (19) ene in 100 ml of chloroform »ft 11.51 g (66.7 mmol) of m-chloro-peroxy-benzoic acid warm to room temperature »Stir for 10 ° C and leave for 24 hours at room temperature» Filter the precipitate, and wash the filtrate with concentrated sodium carbonate solution »several

Dry the organic phase over magnesium sulfate and evaporate in

vacuum. Chromatograph the residue on silica gel (hexane / ethyl acetate 15sl eluents).

Financing 8.76 g (87% of theoretical value) of a colorless oil.

Analysis (referring to the anhydrous compound)?

C73.41 Hl2.32 calculated

873.28 Hl 2.41

b) 10- (2-Hydroxy-11-methoxy-undeci1) -1,4,7-tris-carboxymethyl1-1,4,7,10-tetraazacyclododecane

In analogy to example 4a), 1,2-epoxy-11-methoxy-undecane was used in place of the epoxide used in exemp3. the 4a) «

Yields 75% of the theoretical value of a glazed composition.

Analysis (referring to the anhydrous compound)?

857.12 H9.22 N10.25 calculated

C57.01 H9.34 N10.12

c) Gadolinium complex of 10- (2-hydroxy-11-methoxy-undecyl) -1,4,7-tri s-carboxymethyl 1-1,4,7,10-tetraazacyclododecane

In analogy with example 4b) the compound of example 5ta) was used for complexation instead of the compound of example 4a) „

Yields 97% of theory of a love fo p O _s inco1or.

Analysis (referring to the anhydrous compound) s

C44.55 H6.7 is N8.00 8d22.43 calculated

C44.40 H6.83 N7.87 8d22.31

d) 10- (2-hydroxy-11-methoxy-undecyl) -1,4,7-tris-carboxymethyl1-1,4,7,10-tetraazacyclododecane disprosium complex

In analogy to example 5c), disprosium oxide was used instead of gadolinium oxide.

Yields 97% of the theoretical value of an amorphous powder.

Analyze (referring C44.22 H6.71 C44.10 Hé, S3 EKEMPLO 6

N7

W7

Dy23.01

,) ·, / -? ·? 87 t ~ S - Jw. y \ _í l calculated

a) l-HldeâKÍ-9-bensi1oxy-nonane

Dissolve · 16 g (100 ml) of nonana1,9-dial in 150 ml of dimethylformamide and add · dropwise to a suspension of 2.88 g (1.20 mmol) of sodium hydride in 100 ml of DMF . Cook for 2 hours

50 ⁰ C. Cool in an ice bath at 0 ° C, and add dropwise over 3 hours 1 ', 1 g (100 mmol) of bensyl bromide. Then stir for 5 hours at 60 ° C. Cool the solution to room temperature, add 1 l of water, and extract 3x with 150 ml of ether. Dry the combined organic phases over magnesium sulfate and evaporate in vacuo.

Chroma t oq r fare the oil remaining on silica gel (hexane / acetone eluents. 15s 1) „

Theoretical yields) of a colorless oil.

Analysis (for anhydrous compound) s

C7ô, 75 H10.47 calculated

C76.63 Hl0.53

b) 1,2-Epoxy-4-oxa-13-benzyloxy-tridecane

To 31 g (123.74 mmol) of l-hydroxy-9benzi1oxy — nonane in 400 ml of dimethylformamide, add 3.56 g (148.5 mmol) of sodium hydride and stir for 1 hour at room temperature (under nitrogen). Add 34.35 g (371.22 mmol) of epichlorohydrin, then heat for 24 hours at 70 ° C „Cool in an ice bath at 0 ° C, and carefully add 800 ml of water., Then extract 2x with 350 ml of ether respectively. Dry the combined ether phases over magnesium sulfate and evaporate in vacuo. Chromatograph the residue on silica gel (hexane / ethyl acetate eluents = 20sl).

16.53 g (66% of the value

Yields q (71% of theoretical value) of a colorless oil.

Ι '-'. '., -. Ί

Analysis (referring to the anhydrous compound) s

C / 4.47

H9.87 H9.98 uaiculate

c) 10- (2-Hydroxy-4-oxa-13-benzyloxy-tridecyl) -1, 4,7-tris-carboxymethyl-1,4,1,10-tetraazacyclododecane

In analogy to example 4a) the compound of example 6b) was used in place of the epoxide used in example 4a).

Yields 68% of the theoretical value of a glazed compound »

Analysis (for anhydrous compound) s # ·· * z · * ύ ~ π ·? Uo0, f 1 C60.55

HS, 65 H8 »74

IMS, 58 M8 »47 calculated

d) Gadolinium complex of 10- (2-Hydroxy-4-oxa-13-ben2yloxy-tridee 1) -1,4,7-tris-carboxymethyl 1-1,4,7,10-tetraazacyclododecane

In analogy with example 4b) the compound of example 6c) was used for complexation instead of the compound of example 4a) »

Yields 95 ’% of the theoretical value of a glazed compound»

Analysis (referring to the anhydrous compound) ?,

C49.11 146.62

H6, 73

C49.02

M6.94

N6.85 d 19, 48 falls uu.

Gd 19.31

EXAMPLE 7

10- (2,13-Dihydrósl-4-oxa-13-trideei1) -1,4,7-tri s-carboxymethyl 1 · -1,4,7,10-tetraazacyclododecane

Dissolve q (18.59 mmol) compound of example 6d) in a mixture of 100 ml of water / 100 ml of ethanol and add 3 g of palladium hydroxide (Pear1rnan catalyst), Then hydrogenate under normal pressure at 40 ° C (after 2 hours complete transformation of chords with HPLC) »Filter the catalyst and evaporate! ·· the filtrate to dryness in vacuum,

Yields 13.06 g C98 ’% of theoretical value)

Analysis si C43,56 C43,41

of an amorphous, colorless powder ,, (referring to the anhydrous compound):

H6.61 M7.8Í 6021.93

H6.79 N7, ΔG 6d21.80 cal cu3. ado

EXAMPLE 8

a) 10- (2,6,7, -Trihydroxy-4-oxa-heptyl) -1,4,7-tris-carboxymethyl 1-1,4,7,10-tetraazacyclododecane

In analogy to example 4a), 2,2-dimethyl -4- (2 · ', 3'-epoxy) -proxymethyl 1 -1,3— di οχ o 3. used in 1 ug ep o xidouti air 1 iz ad ο η o ex emp 1 o 4a) »

Yields 71% of the theoretical value of a colorless compound.

Analysis (referring to the anhydrous compound) s

C4S, 57 H7.74 Ml1.33 calculated

C48.46 H7, S1 N11.24

b) Gadolinium complex of 10- (2,6,7, -Trihydroxy-4-oxa-bepti1) -1,4,7-tris-carboxymethyl1-1,4,7,10-tetraazaeielododeeano

In analogy with example 4b), the compound of example Sa) was used for complexation instead of the compound of example 4a) »

Yields 98% of the theoretical value of an amorphous powder »

Analysis (referring to the anhydrous compound) s

C37.03 H5.44 N8.64 Sd24.24 calculated

C37, G0 H5,5Í IMS, 57 Gd24,18

c) Europium complex of 10- (2,6,7, -Trihydroxy-4-oxa-hepti1) -1,4,7-tris-carboxymethyl-1,4,7,10-tetraazacyclododecane have analogy with ex emp1u 8b ) europium oxide was used instead of gadolinium oxide.

Yields 96% of the theoretical value of an amorphous powder »

Analysis (referring to the anhydrous compound) s

H5.48

H5.53

IMS, 71 NS, 66

Eu23,56: al cul ada • ~? Q

d) Dysprosium complex of 10- (2,6, Ί, -Trihydroxy-4-oxa-hepti1) -1,4, 7-tri g-carboxy raeti 1-1,4,7, 10-tetraasacyclododecane

In analogy to example 8b), dysprosium oxide was used instead of gadolinium oxide »

9 &% of the theoretical value of an amorphous powder »

Analysis (referring to the anhydrous compound)?

C36 ₅ 73

H5 ₅ 39

SM8 ₅ 57

N8 „51

Dy24.85 Dy24.80 calculated

s) 10- (2,6,7, -Trihydroxy-4-oxa-hepti1) -1,4,? -tris-carboxymethyl 1-1,4,7, 10-tetraasaeiclododecane ytterbium complex

In analogy with example Sb) ytterbium oxide was used instead of gadolinium oxide »

Yield? 97% of the theoretical value of an amorphous powder »

Analysis (referring to the anhydrous compound)?

H5.31

Ηκ; · o O

-J η jl- \ 2i

IMS, 43 IMS, 38

Yb26 ,! 04 ca 1 cu 1 ado

EXAMPLE 9

a) 2,5,8,13,16,19-Hexoxaeicos-10-ene

To 40 gdi eti1enog1i col-monomethanol (mmol) are 500 ml of dimethylformamide, add 8.79 g (366.2 mmol) of sodium hydride and stir for 1 hour at room temperature »Add 23.74 g (11.1 mmol) of ci s-1,4-di bromo-butene, and heat for 24 hours at 70 ”C,

Cool in a gel bath at 0 ° C, and carefully add 1000 ml of water »Then extract 2x with 400 ml of ether respectively» Wash to dry on Cr omat with different ethereal ashes Ix with 200 ml of water, evaporate if 1icaqel in the vacuum »(eluent?

15.25 g (47% of the magnesium ulfate value and the residue on hexane / ethyl acetate = 20? D »

Theoretical yields, in relation to dibromo-butene) of a colorless oil Analysis (referring to the anhydrous compound)?

C57.51 H9.65 calculated

C57.58 H9.57

b) 10,11-Epoxy-2,5,8,13,16,19-hexoxaeicosane

Dissolve 15 g (51.3 mmol) of the compound of example 9a) in 100 ml of chloroform »At 0 ° C add 11.51 g (66.7 mmol) of m-chloro-peroxy-benzoic acid and allow to warm to the temperature room »Shake for 24 hours at room temperature» Filter the precipitate and wash the filtrate several times with concentrated sodium carbonate solution »Dry the organic phase over magnesium sulphate and evaporate in vacuo» Chromatograph the residue on silica gel (eluent ·. hexane / ethyl acetate = 15s1) »

Yields 1-.5,76 g (8 /% of theory) of a colorless oil »

Analysis (referring to the anhydrous compound) s C54.53 H9.15 calculated

C54.47 H9.06

c) 10- [1- (2,5, S-Triaxanani1) -2-hydroxy-4,7, IG-tr1oxa-undecanyl)] -1, 4,7-tris-carboxymethyl-1, 4.7 , IQ-tetraazacyclododecane

In analogy to example 4a) 10,11-epoxy-2,5, S, 13,16,19-hexoxaeicasane was used in place of the epoxies of the user ex emp1o 4a) »

Yields 34% of the theoretical value of a compound compound »Analysis (referring to C5i, 36 HS, 31

C51.27 H8.40 anhydrous compound) s

N Y, 56 calculated

IMS, 51

d) Gadolinium complex of 10- [l- (2,5,8-Trioxanonyl) -2-hydroxy-4,7,10-trioxa-undecanil)] - 1,4,7-tris-carboxymethyl1-1,4 , 7,10-tetraazacyclododecane

In analogy with example 4b) the compound used instead of the compound of example 4a) was used for complexation.

Renewal 97% of Example 9c) in 1 orte of an amorphous, colorless powder An ál se (refer to C41,57 H6,35

C41.4S H6.41 anhydrous compound) s

6.93 Gd 19.44

N6.91 Bdl9.37 calculated

EXAMPLE 10

a) 9 _f 14-dioxa-docos (11) and n

In analogy to example 9a) n-octanol was used instead of ether · diethylene glycol-monomethyl »

Yields 59% of the theoretical value of an oil i nco1or.

Analysis (referring to the anhydrous compound) s

076.86 HÍ2.90 calculated

076.78 H12.84

b) 11.12-Epoxy-9.14-dioxa-docosane

In analogy with example 9b)

the compound of example 10a) was used in place of the compound example 9a) » Healthy Ren d % of theoretical value an oil i n c o 1 o r » Analyze (r e f e r e n t e a o c ompto rt an i d r o 5 s 073.12 Hl2,27 calculated 073.04 H1.2,34

c) 10- [1- (2-oxadic 1) -2-hydroxy-4-oxa-dodecyl] -1, 4,7-tris-carboxymethyl1-1,4,7,10-tetraazacyclododecane have an analogy with the above 4a ) 11,12-epoxy-9,14-dioxa-docasa.no was used instead of epoxide used in example 4a) »

Yields 37% of the theoretical value of a colorless compound »

Analysis (referring to the anhydrous compound) s

060.51 H9.86 N8.30 calculated

060.46 H9.94 N8.25

d) Gadolinium complex of ÍQ- [l- (2-oxadecyl) -2-hydroxy-4-oxa-dodecyl] -1, 4,7-tris-carboxymethyl 1-1,4,7,10-tetraazacyclododecane

In analogy with example 4b) the compound of example 10c) was used for complexation in

place of the compound of example 4a) '

Yields 96% of the theoretical value of a colorless powder.

Analysis (referring to the omp ost o an id ro) s

N6.76 Gd 18.97 calculated

C49.25 C49.17

H7.66 H ?, 80

N6.68

Gd 18.91

EXAMPLE 11

a) 10- (2-Hydroxy-5-phenyl-4-oxa-pentyl) -1,4,7-tris (carboxymethyl) - !, 4,7, 10-tetraasacyclododecane

Dissolve 1, 2 g (2) 9.45 mmol) of 1,4,7-tricarboxymethyl1-1,4,7,10-tetraazacyclododecane (= D03A) and S, 7 g (53.0 mmol) of benzyl ether 3 -2,3-epoxypropyl in a mixture of 50 ml of dioxane and 80 ml of water, and adjust to pH 10 with 6N KOH. Stir for 24 hours at 40 ° C. Evaporate to dryness, recover the residue with 200 ml of water / 50 ml of methanol and extract 2x with 100 ml of t-butyl ether-ether. Adjust the solution with 5N HCl and evaporate to dryness.

Concentrate the compound with a vacuum evaporate, aqueous to pH 3 residue in a vacuum and boil (extract) the residue with 200 ml of methanol / 50 ml of methylene chloride. Cool in an ice bath and filter the precipitated potassium chloride. Evaporate the filtrate in vacuo, dissolve the residue in 45 ml of water and then pour over a poly- (4-vinylpyridine) column. Elute ethanol / water solution 5. After obtaining 11.58 g (77% of theory) of a glassy, highly hygroscopic compound.

Analysis (referring to the anhydrous compound) s

H7.50 Ni0.97 calculated

H7.58 NIC, 81

b) 10- (2-Hyddxi-5-pheni1-4-oxa-pentyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane gadolinium complex

Dissolve 10.0 g (19.59 mmol) of the compound of example 11a) in 70 ml of deionized water and add 3.55 g (9.79 mmol) of gadolinium oxide. Heat 3 hours at

90 ° C.

Stir the cooled solution for 1 hour at room temperature

environment with 3 ml of acidic ion exchange resin (IR 120) &

ml of alkaline ion exchange resin (IRA 410). After filtering the resins, lyophilize the filtrate.

Theoretical yields) of an amorphous powder.

Analysis (referring to the anhydrous compound) s

12.5 q (96% of the value

043.31

H5.31 H5.37

NS, 43 N8.41

8d23.65

Sd23 „58 calculated

c) Europium-pentyl ^lcl complex) -1,4,7-tris (carboxy methyl) -1,, 4,7, 10-tetraazacyclodode

In analogy to the example (1b) oxide of ^{i = si} europium was used instead of gadolinium oxide.

Yields 95% of the theoretical value of an amorphous powder.

Analysis (for anhydrous compound) §

NS, 63 Eu23.54

N8.73

10- (2-Hydroxy-5-phenyl-4-oxaIn · * · «Tm. Π I i-í ^ 1 ι lrj .U Vn.‘

Calculated H5.10

d) 10- (2-Hydroxy-5-phenyl-4-oxa-pentyl) -1,4,7-tris (carboxymethyl) -1,4,7, 10-tetraazacyclododecane ytterbium complex

In analogy to example 11b) ytterbium oxide was used instead of gadolinium oxide.

Yields 98% of the theoretical value of an amorphous powder.

Analysis (referring to the anhydrous compound) s

NS, 41 Yb25.96 c a1c u1ad o

C41.37

H4.99 H5.05

NS, 37 vuoc: o 1 i L4 «sZ · - ^s π 4.

EXAMPLE 12

a) 10- [3- (4-Nitrophenoxy) -2-hydroxypropyl] 1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

Dissolve 12.68g (64.95 mmol) of 4-nitrophenyl-2,3-epoxypropyl ether and 12.5 g (36.08 mmol) of 1,4.7 — triscarboxymethyl-1,4,7,10-tetraazacyclododecane (= D03A) in a mixture of 70 ml of dioxane and 80 ml of water, and adjust the

ρΗ 10 with ΚΟΗ 6Ν „Stir for '24 hours at 40 ° C. f steam to dryness, recover the residue with 200 ml of water / 50 ml of methanol and extract 2x with 100 ml of aqueous ethyl acetate at pH 3 with 5N HCl and evaporate the residue in a vacuum and -Ferver (extract) it, solution to dryness. Focus the with

200 ml of methanol / 50 ml of methylene chloride. Cool in an ice bath and filter the precipitated potassium chloride.

filtered in vacuo, dissolve the residue in 50 ml of water / 30 ml of ethanol, and then pour over a column of poly- (4-vinylpyridine). Elute the compound with a ls4 ethanol / water solution. After evaporating in a vacuum, 14.43 g (74% of theoretical value) of a glassy, highly hygroseopic compound is obtained.

Analysis (referring to the anhydrous bond)?

051.11 H6.34 N12.96 calculated

C51.07

H6.41

NI2.96 N12.90

b) Gadolinium complex of 10- [3- (4-Nitrophenoxy) -2-hydroxypropyl] 1,4,7-tris (carboxymethyl) -1,4,7,10-tetraasacielododecane

Dissolve 14.1 g (26.08 mmol) of the compound of example 12a) in 100 ml of deionized water and add 4.73 g (13.04 mmol) of gadolinium oxide. Heat 3 hours at 90 ° C. Stir the cooled solution for 1 hour at room temperature with 3 ml of acidic ion exchange resin (IR 120) and 3 ml of alkaline ion exchange resin (IRA 410). Filter the resins and evaporate to dryness under vacuum.

Ren d i es s (theoretical 7.4 g) of a glazed compound.

(96% of the

Analysis (referring to

C39.70 with an an d y compound) 5

N10, Otí Gd 22,63

1410.12: calculated

Gadolinium complex of 10- [3- (4-aminophenoxy) -2-hydroxypropyl] -1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraasacyclododecane

Hence1 see 15.0 g (2'-h, 59 mmol)

compound of example 12b) in 250 ml of deionized water and add 3 g of palladium catalyst (10% Pd on active carbon). Hydrogenate at 40 ° C for 2 hours (complete transformation according to HPLC). Filter the catalyst and evaporate the filtrate to dryness in vacuo.

Yields 14.07 g (98% of theoretical value) of a glazed compound.

Analysis (referring to the anhydrous compound):

Niú, S3

Gd23.58

Gd23,65 c a 1 u 1

C4Í, 50

H5.09

Ml0.49

d) Gadolinium complex of 10- [3- (4-isothioeyanatophenoxy) -2 · -hydroxypropyl] -1, 4,7-tris (carbosimethyl) -1,4,7,10-tetraazacyclododecane g (lo, o4 ίϊϋίϊοΐ) of poly vi nil ~ pi r idi na

Dissol see compound of example 12c) and 30 ml of (Reillex) in 200 ml of deionized water and add 5.19 g (45.13 mmol) of thiogenic) in 150 ml of chloroform) „Stir 10 minutes at 40 ° C, then 1 hour at room temperature. Filter the Reillex from the solution, and separate the organic phase. Extract the aqueous phase 2x as 100 ml of chloroform and then lyophilize.

Theoretical yields) of a white, amorphous powder.

Analysis (referring to the anhydrous compound):

10.31 q (97% of the value

C40.78 C40.67

H4.42

H4.51

N9.91

N9.85

Gd22,25 Gd22,19

S4.54

S4.48 falls guilty

EXAMPLE 13

a) 10- (2-Hydroxy-3-fenosi-propyl) -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

Dissolve 7.8 g (51.98 mmol) of phenyl 1-2,3-epoxypropyl ether and 10 g (28.87 mmol) of 1,4,7-triscarboxymethyl1-1,4,7,10 — tetraazacyclododecane <= D03A> in a mixture of 50 ml of dioxane and 80 ml of water, and adjust to pH 10 with KOH 8N „Stir for 24 hours at 40 ° C. Evaporate to dryness, recover the residue with 200 ml of water / 50 ml of methanol and extract with

100 ml of t-buti1-methyl ether »Fix the solution

aqueous to pH 3 with 5iM HCl and evaporate to dryness »residue in vacuo and -Ferver (extract) the residue with methanol / 80 ml of methylene chloride» Cool the cock and filter the precipitated potassium chlorate »filtered in vacuo, dissolve the residue in 50 ml and ethanol, and then pour over a column Elute the compound with a

After evaporating in a vacuum, 8.17 g (57% of theory) of a glazed compound are obtained, strongly hygroscopic »

Analysis (regarding anhydrous compound)?

calculated

Níl, 24

-vi ni1p i ri di na) »ethanol / water 1s3»

Focus ο

200 ml in in bath in Evaporate O ; water / 20 ίϊΐ I ie poli- (4— solution in

H7.31

H7 „38

b) Gadolinium complex of 10- (2-Hydroxy-3-phenoxy-propyl) -1, 4,7-tris (carboxymethyl 1) -1,4,7,10-tetraasacyclododecane

Dissolve 7.8 g (15.71 mmol) of the compound of example 13a) in 50 ml of deionized water and add, 85, 85 mmol) of gadolinium oxide »Heat 3 hours at

90 ° C »Stir the cooled solution for 1 hour at room temperature with 3 ml of acidic ion exchange resin (IR 120) and 3 ml of alkaline ion exchange resin (IRA 410), filter the resins, lyophilize the filtrate»

Yields 9.71 g theoretical) of an amorphous, colorless powder »

ANAI: i. if C refers to the anhydrous compound) C42.45 H5, ll IMS, 61 Sd24,16

After (95% of the C42.38 value

H5.11 H5 »19

IMS, 61 N8.56

Bd24.09 culinary lime

EXAMPLE 14

a) 10- [2-Hydroxy-3- (4-methoxyphenoxy) -propyl] -1,4,7-tris (carboxymethyl 1) -1,4,7,10-tetraazacyclododecane

Dissolve 9.36 g (51.96 mmol) of 4-methoxy-phenyl ~ 2,3-epoxypropyl ether and 10 g (51.96 mmol) of 10-tetraazacyclododecane i, 4,7-tri scarboxi met i I -1 in a mixture of 50 ml of dioxane and 80 ml of water, (D03A>

and adjust pH 10 with 6N KOH »Stir for 24 hours at 40 ° C» Evaporate36

dryness, resume the res i duo with 200 to extract 2x with 100 ml in ether solution watery a pH 3 with H81 Concentrate air or res residue at the \ / acid and f

u t; a y í..i a / · .j v ί n x and i h e u a n o. ·. and -buti 1 -mst ί 1 i co. Set at 5N and evaporate to dryness.

200 ml of methanol / 80 ml of methylene chloride. Cool in an ice bath and filter the precipitated potassium chloride. Evaporate the filtrate in vacuo, dissolve the residue in 45 ml of water / 20 ml of ethanol, and then pour over a poly- (4-viniIpiridine) column. Elute the compound with an ethanol / water solution 3. After evaporating in vacuo, 9.27 g (61% of theory) of a glazed compound are obtained, strongly hygroscopic.

Analysis (regarding anhydrous filler)?

calculated ~ r η j ~ r

854.71

NIO, 46 NIO, 57 l i i η A. I

H7 „30

b) Gadolinium complex of 10- [2-Hydroxy-3- (4-methoxyphenoxy) -propyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraasacyclododecane

Dissolve 8.8 g (16.71 mmol) of the compound of Example 14a) in 60 ml of deionized water and add 3.03 g (8.36 mmol) of the gadolinium oxide. Heat 3 hours to 90 * 8. Stir the cooled solution for 1 hour at room temperature with 3 ml of acidic ion exchange resin (IR 120) with 3 ml of alkaline ion exchange resin (IRA 410). After filtering the resins, lyophilize the filtrate.

Yield? 11.04 g (97% of theory) of an amorphous, colorless powder.

Analysis (referring to the anhydrous compound)?

842.34 H5.18 NS, 23 Gd23.10 calculated

842.28 H5.23 N8.17 Gd23.03

EXAMPLE 15

a) 6,7-Epoxy-4-oxa-1- [4- (methoxy) -phenyl] -heptane

In analogy with example 6b) use 3- (4-methoxyphenyl) -propan-1-ol in place • example 6a).

of the compound the

Yields 38% of the theoretical value of a viscous oil, ncolor.

Analysis (referring to the anhydrous compound):

C70.24 H8.16 calculated

C70.3i H8.20

b) 10- [2-Hydroxy-4-oxa-7- (4-methoxyphenyl1) -hepti1] -1,4,7-tris (carboxymethyl 1) -1,4,7, 10-tetraazacyclododecane

Dissolve 10.93 g (51.96 mmol) of 6 ₅ 7 “epoxy“ -4 “Oxa ~ l-C4” (methoxy) -phenyl 1 3-heptane and 10 g (28.87 mmol) of 1.4 , 7-tri scarboxi met i 1 -1,4,7,10-tetraazaci codododecane (“D03A) in a mixture of 60 ml of dioxane and 90 ml of water, and adjust to pH 10 with 6N KOH = Stir for 24 hours at 40'C. Evaporate to dryness, take up the residue with 200 ml of water / 50 ml of methanol and extract 2x with 100 ml of t-butyl methyl ether. Adjust the aqueous solution to pH 3 with 5N HCl and evaporate to dryness, Concentrate the residue in vacuo and boil (extract) the residue with 200 ml of methanolZ80 ml of methylene chloride. Cool in an ice bath and filter the precipitated potassium chloride. Evaporate the filtrate in vacuo, dissolve the residue in 45 ml of water / 20 ml of ethanol, and then pour over a column of poly- (4-vi ni 1 pyrine). Using a solution of ethanol / water ls3, After evaporating in a vacuum, 9.69 g (59% of theoretical value) of a glazed compound are obtained, with strong hygroscopic strength. .

Analyze C57.03 C57.10 (referring H7.80 H7.85 anhydrous compound) s N9.85 N9.79 calculated c) Complex of gadolinium 10- [2-Hydroxy-4-oxa-7

-metoxyphenyl) -hepti1] -l, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

Dissolve 9.2 g (16.18 mmol) of the compound of example 15b) in 80 ml of deionized water and add 2.93 g (8.09 mmol) of the gadolinium oxide. Heat 3 hours to 90 ° C. Stir the cooled solution for 1 hour & room temperature with 3 ml of acidic ion exchange resin CIR 120) and

ml of alkaline ion exchange resin (IRA 410). After filtering the resins, lyophilize the filtrate »

Yields 13.34 g (97% of theory) of an amorphous, colorless powder »

Analysis (referring to the anhydrous compound);

C44.86 H5.72 N7.75 Gd21.75 calculated

044.79 H5.81 N7.69 8d21.6S

EXAMPLE 16

.) 10- [3- (4-Chlorophenoxy) -2-hydroxypropyl] -1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

Dissolve 9.59 g (21.96 mmol) of 4-chlorophenyl1-2,3-epoxypropyl ether and 10 g (28.87 mmol) of

1,4,7-triscarboxy meti1-1,4,7,10-tetraazacyclododecan (= D03A) in a mixture of 50 ml of dioxane and 80 ml of water, and adjust to pH 10 with 6N KOH »Stir for 24 hours at 40 ° C »Evaporate to dryness, take up the residue with 200 ml of agus / 50 ml of methanol and extract 2x with 100 ml of t-butyl ~ methyl ether» Adjust the aqueous solution to 3 µl with 5N HCl and evaporate to dryness,

Concentrate the residue in a vacuum and boil (extract) the residue with 200 ml of methanol / 80 ml of methylene chloride »Cool in an ice bath and filter the precipitated potassium chloride» Evaporate the filtrate in vacuo, dissolve the residue in 45 ml of water / 20 ml of ethanol, and then pour over a column of poly ™ (4-vini1 pyridine) »Elute the compound with a solution of ethanol / water is 3, After evaporating in vacuo, 8 , 28 g (54% of theory) of a glazed, highly hygroseoptic compound »

Analysis (referring to the anhydrous filler);

Cl 6.68 calculated

Cl 6.60

C52.02 H6.64 Hl0.55 C52.05 H6.71 Hl0.49 B) Complex of gadolinium

do 10- [3- (4-Chlorophenoxy) -2-hydroxypropyl] -1, d, 7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

Dissolve 7.9 g (14.88 mmol) of the compound of Example 16a) in 60 ml of deionized water and add

2.70 g (7.44 mmol) of gadolinium oxide. Heat 3 hours 90 * C. Stir the cooled solution there for 1 hour at room temperature? environment with 3 ml of acidic ion exchange resin (IR 120) ml of alkaline ion exchange resin (IRA 410). After c fi i11 resize, 1 iofiIize the i11 rad o »

Yield:

theoretical) of an amorphous, colorless powder »

Analysis (referring to the anhydrous compound):

Ο “Ό. ·, I t (96% of va:

ie

C40.32

NS »li

Cl 5 »17 calculated

H4, SONS, 09

C15.10

EXAMPLE 17

a) 2,3-EpãKi-l- [4-hydroxypentyl) “phenoxy] -propane

In analogy to example 6b) use 5- (4 ..... hydroxyphenyl1) -pentan-l-ol in place of the compound of example 6a) »

Yield: 51% of the theoretical value of one 1. and the i n c o 1 o r »

Analysis (referring to the anhydrous compound):

C71.16 HS, 53 calculated

C7í, 0S HS, 62

b) 10- [2-Hydroxy-3- (4- (5-hydroxypenti1) -phenoxy) -propyl] -1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

Dissolve 12.3 g (51.97 mmol)

2,3-epoxy ”1-C4“ (5-hydroxypenti1) -phenoxy3-propane and 10 g (28.87 mmol) of 1,4,7-triscarboxy methyl 1-1,4,7,10-tetraazacyclododecane (= D03A) in a mixture of 50 ml of dioxane and 80 ml of water, and adjust to pH 10 with KOH 6N »Stir for 24 hours at 40 * C» Evaporate to dryness, recover the residue with 200 ml of water / 50 ml of methanol and extract 2x with 100 ml of t-butyl methyl ether »Adjust the pH 3 aqueous solution with 5N HCl and evaporate to dryness» Concentrate the residue in vacuo and boil (extract) the residue with 200 ml of methanol / 50 ml of methylene chloride »Cool in an ice bath and filter the precipitated potassium chloride» Evaporate the filtrate in vacuo, dissolve the residue in 50 ml of water / 20 ml of ethanol, and then pour over a column of

IliSílQj. ? Lite!

poly- (4-vinylpyridine). Elute the compound with a ls3 ethanol / water solution. After evaporating in a vacuum, 8.92 g (53% of theory) of a glassy, highly hygroscopic compound are obtained.

Analysis (referring to the anhydrous compound) s

C57.72 H7.72 N9.62

C57.68 H7.79 N9.54 calculated

c) 10- [2-Hydroxy-3- (4- (5-hydroxypentyl) -phenoxy) -propyl] -1, 4,7-tris (carboxymethyl 1) -1,4,7,10- gadolinium complex tetraazacyclododecane

Dissolve 8.7 g (14.93 mmol) of the compound of example 17b) in 70 ml of deionized water and add 2.71 g (7.47 mmol) of gadolinium oxide. Heat 3 hours at 90 ° C „Stir the cooled solution for 1 hour at room temperature with 3 ml of acidic ion exchange resin (IR 120) and 3 ml of alkaline ion exchange resin (IRA 410). After filtering the resins, lyophilize the filtrate.

Yields 10.67 g (97% of value) of an amorphous, colorless powder.

Analysis (referring to the anhydrous compound)?

C45.64 H5.88 N7.60

C45.60 H5.93 N7.54

Sd 21.34 ca1cu1ad o

Gd2i, 28

EXAMPLE 18

a) 10 - [3- (2,6-Dimethylphenoxy) -2-hydroxypropyl] -1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

Dissolve 9.59 g (51.96 mmol) of 4-chlorophen ether, i 1 -2,3-epoxypropyl and 10 g (28.87 mmol) of

1,4,7-triscarboxymethyl 1-1,4,7,10-tetraazacyclododecane (= D03A) in a mixture of 50 ml of dioxane and 80 ml of water, and adjust to pH 10 with 6N KOH. Stir for 24 hours at 40 ° C. Evaporate to dryness, take up the residue with 200 ml of water / 50 ml of methanol and extract 2x with 100 ml of t-butyl methyl ether. Adjust the aqueous solution to pH 3 with 5N HCl and evaporate to dryness. Concentrate the residue in a vacuum and boil (extract) the residue with 200 ml of methanol / 80 ml of methylene chloride. Cools · - · in

ice bath and filter the precipitated potassium chloride »Evaporate the filtrate in vacuo, dissolve the residue in 50 ml of water / 30 ml of ethanol, and then pour over a column of poJ (4-vin i1p ir idi na) • lui: composed with a solution of ethanol / water Is 3 »After evaporating in a vacuum, 9.24 g (61% of theoretical value) of a glazed compound, strongly hyg rosic acid, are obtained»

Analysis (referring to C57.24 H7.68

857.18 H7.74 anhydrous compound) s

Calculated N10.68

N10.64

b) Gadolinium complex of ÍQ- [3- (2,6-Dimethylphenoxy) -2-hydroxypropyl] -i, 4,7-tris (carboxymethyl) -1,4,7,10-tetraasacielododeean

Dissolve 9.0 g (17.16 mmol) of the compound of example 18a) in 70 ml of deionized water and add 3.11 g (8.58 mmol) of gadolinium oxide »Heat 3 hours at 90 ° 8« Stir solution cooled for 1 hour at room temperature with 3 ml acidic ion exchange resin (IR 120) and 3 ml alkaline ion exchange resin (IRA 410) »After filtering the resins, lyophilize the filtrate.

Theoretical yields) of an amorphous, colorless powder »

Analysis (referring to the anhydrous compound)?

844.23 H5.49 N8.25 Gd23.16

844.18 H5

11.30 q (97% of the value .1 cul de

IM ΣΣ ·, ~~ N8,20

Gd23 »08

EXAMPLE 19

a) 2,3-Epoxy-1- [4- (ethoxycarbonylmethyl) -phenoxy] -propane

In analogy to example 6b) use ethyl 4-hydroxyphenyl-1 acetate instead of the compound of example 6a) »

Yields 61% of va3. oror of an o 1 and the v: i. scoso, i ncol or »

Analysis (referring to the anhydrous compound) s 866.09 H 6.8 3 caloulado

866.14- Hô, 74

b) 10- [2-Hydroxy-3- (4- (carboxymethyl) -phenoxy) -propyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

D i s s 1 v e r 10 çj (28,, 87 mmol) of

1,4,7-trisearhoximetiI "-l, 4,7,10-tetraazacyclododecane (= DD3A) and 12.99 µl (51.96 mmol) of 2,3-epoxy-1-E4- (2-ethoxy icarboni lmeti 1) -phenoxy3-propane in a mixture of 80 ml of dioxane and squa, adjust to pH 13 with KQH 6IM »Stir for 12 hours at room temperature and then boil under reflux for hours» Adjust to pH 7 with HCl 5N and evaporate to vacuum dryness »

Purify the residue with 200 ml of ethanol / 50 ml of chloroform

60 ° C «Filter the precipitated potassium chloride and evaporate the filtrate in vacuo» Purify the residue on a reverse phase column (RP-18, wash with water, then elute with tetrahydro-furan / water = 2sl) = Evaporate the main fractions in a vacuum »

Yields 8.32 g (52% of theory) of a glazed compound »

Analysis (referring to the anhydrous compound)?

Calculated N10.10

N1V, 0 &

C54.14 C54.06

H6.91 H6 „98

c) Gadolinium complex of 10- [2-Hydroxy-3- (4- (carboxymethyl) -phenoxy) -propyl] -1, 4,7-tris (carboxymethyl 1) -1,4,7,10-tetraasacyclododecane ( sodium salt)

Dissolve 8.1 g (14.61 mmol) of the compound of the example: i.9b) in 60 ml of deionized water and add 2.65 g (7.30 mmol) of gadolinium oxide, iwass

90 ° C »Stir the cooled solution for 1 hour at room temperature with 7 ml of slightly acidic ion exchange resin (AM.B 252c)

F i 11r the resin,

Yield?

theoretical) of an amorphous, colorless powder. Analysis (for anhydrous compound)

Set the filtrate to pH

10.14 g (95% of the value

C41.09 C4Í, 04

H4.78 u / **? N f q £ 3 í

N7.61

Gd21.52

Na3,15 cul culado

EXAMPLE 20

a) 2,3-Epoxy-1- [4- (ethoxycarbonyl} -cyclohexyloxy] -propane

In analogy with example e) use ethyl 4-hydroxy ..... cyclohexane-carboxylate in place of the compound of example 6a).

Ren d i men t § 33% d o va I or t e r i c: o d e

an oil incoior » Analyze (referring 863.14 H8.33 Γ'Ζ. “3 Λ’ · ' t} V i H8.91

ta) 10- [2-Hydroxy-3- (4- (carboxy) -cyclohexyloxy) -propyl] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraa2acyclododecane

Dissolve · 10 g (28.87 mmol) ds

1,4,7-tr i sound box i met i 1 - 1,4,7,10-tetr aaz ac x o 1 ododecane (= D03A) and

12.99 g (51.96 mmol) of 2,3-epoxy-1-E4- (2-ethoxycarbonyl) -cyclohexyloxy-3-propane in 80 ml of dioxane / 60 ml of water, and adjust to pH 13 oom KOH 6N. Stir for 12 hours at room temperature, then boil under reflux for 2 hours. Adjust to pH 7 with HC1 SN and evaporate to dryness under vacuum. Stir the residue with 200 ml of ethanol / 50 ml of chloroform at 60 ° C. Filter · the precipitated potassium chloride and evaporate the filtrate in vacuo. Purify the residue on a reverse phase column (RF — 18, wash with water, then elute with tetrahydro-furan / water = 2: 1). Evaporate the main fractions in a vacuum.

Yields 8.2 g (52% of theory) of a glazed compound.

Analysis (referring to the anhydrous compound) s 852.74 H7.74 N10.25 calculated

852.68 H7.81 NÍ0.19

Gadolinium complex of 10- (2-Hydroxy-3- (4- (carboxy) -cyclohexyloxy) -propyl] -1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraazaeielododeeano (sodium salt)

Dissolve 8.0 g (14.64 mmol) of the compound of example 20b) in 70 ml of deionized water and add 2.66 g (7.32 mmol) of gadolinium oxide. Heat 3 hours at

90 ° C »Stir the cooled solution for 1 hour at room temperature with 10 ml of slightly acidic ion exchange resin (CHAM 252c) ,, Filter the resin» Set the filtrate to pH

7.2 with 2N NaOH are freeze-dried »

Yields 9.84 g (93% of value

theoretical) of a powder amorphous, colorless » Analyze (referring anhydrous compound) s C39.88 H5.30 N7.75 Gd21.75 Ma3,13 c a1cu1ad .3 839.81 H5.37 N7.69 Gd21.70 Na3.25 EXAMPLE 21 a) 2,3-Epoxy-1- [4- (2-ethoxycarbonylethi1) -phenoxy] -propane In analogy for example 6b) use 2- · (4-h i drox i f en i 1) -prop 1 onato of ethyl in place of compound from example 6a) » Income 67% of theoretical value in an oil colorless" Analyze (referring anhydrous compound) s CÓ7, Í8 H7.25 calculated C67.09 H7.32

b) i0- [2-Hydroxy-3- (4- (2-earboxyethyl) -phenoxy) -propi1] -1,4,7-tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane

Dissolve 10 g (28.87 mmol) of

1,4,7-triscarboxymethyl-1, 4,7,10-tetraazacyclododecane (= D03A) and

12.99 g (5i, 96 mmol) of 2,3-epoxy —-1 — C4- (2-ethoxy carbonylethyl) —phenoxy3-propane in 80 ml of dioxane / 60 ml of water, and hit the pl-l 14 with 6N KOH »Stir for 12 hours at room temperature, then boil under reflux for 2 hours» Set to pH 7 with 5N HCl and evaporate to dryness in vacuum »Stir the residue with 200 ml of ethanol / 50 ml of chloroform at 60 ° C »Filter the precipitated potassium chloride ε evaporate the filtrate in vacuo» Purify the residue on a CRP-18 reverse phase column, wash with water, then elute with tetrahydro-furan / water = 2si) »Evaporate the main fractions in vacuum"

Yield: 7.8S g (48% of theoretical value) of a glazed compound »

Analysis (referring to the anhydrous compound);

C54.92 H7.09 N9.85 calculated

C54.87 H7.15 N9.79

c) Gadolinium complex of 10- [2-Hydroxy-3- (d- (2-carboxyethyl) -phenoxy) -propyl] -1,4,7-trie (carboxyethyl) -1,4,7,10-tetraasacyclododecane (salt only)

Dissolve 7.5 g (13.19 mmol) of the compound of example 21b) in 50 ml of deionized water and add 2.39 g (6.59 mmol) of gadolinium oxide. Heat 3 hours to 90 ° C. Stir the cooled solution for 1 hour at room temperature with 7 ml of slightly acidic CAMB 252c exchange resin „Filter the resin. Set the filtrate to pH

7.2 with 2N NaOH and lyophilize.

Yields 9.23 g (94% of theory) of an amorphous, colorless powder · »

Analysis (referring to the anhydrous compound);

C41.93 1-14.87 N7.52 Gd21, ll Na3.09 calculated

C41.87 H4.93 M7.47 Sd21.06 Na3.14

EXAMPLE 22

a) 2,3-Epoxy-1- [4- (2-ethoxycarboni1-1-oxa-ethyl1) -phenoxy] -propane

In analogy to example 6b), use ethyl 4-hydroxy-phenoxy-acetate instead of the compound of example 6a) »

Yields 57% of the theoretical value of an oil i ncolor „

Analysis (referring to the anhydrous compound);

C61.89 H6.39 calculated

C61.78 H6.43

b) 10- [2-Hydroxy-3- (4- (2-carboxy-1-oxa-ethyl) -phenoxy) -propyl] -1 _f 4,7-tris (carboxymethyl 1) -1,4,7, 10-tetraazacielododecane

Dissolve 10 g (28.87 mmol) ds

1,4,7 — triscarboxymethyl-1,4,7,10-tetraazacyclododecane (= D03A) and

12.99 g (51.96 mmo 1) of 2,3-epoxy -1 - C 4- (2-stoxic ar bon i 1 st i 1) --phenoxy3 ~ propane in 80 ml of dioxane / 60 ml of water, and adjust the

pH 13 with 6N KOH. Stir for 12 hours at room temperature, then boil under reflux for 2 hours. Adjust to pH 7 with 5M HCl and evaporate to dryness in vacuo. Stir the residue with 200 ml of ethanol / 50 ml of chloroform at 60 ° C. Filter the precipitated potassium chloride and evaporate the filtrate in vacuo. Purify the residue on a reverse phase column (RP-18, wash with water, then elute with tetrahydro-furan / water = 2si). Evaporate the main fractions in a vacuum.

Yields 8.4 g (ol% of theory) of a glazed compound.,

Analysis (for anhydrous compound) s, 6.f .. Ho, f 1

C52.58 H6.78

M9.82

Calculated N9.77

c) 10- [2-Hydroxy-3- (4- (2-carboxy-1-oxa-ethyl) -phenoxy) -propyl] -1,4,7-tris (earboxiroethyl) -1,4 gadolinium complex , 7,10-tetraasaeiclododecane (sodium salt) (14.2 mmol) of

Dissolve 8.1 g compound of example 22b) in 70 ml of deionized water and add 2.57 g (7.1 mmol) of gadolinium oxide. Heat 3 hours at 90 ° C. Stir the cooled solution for 1 hour at room temperature with 10 ml of resin lightly Filter the resin. Set scics to exchange the filtrate at pH

7.2 with 2N SMaOH and freeze-dry.

Theoretical yields) of an amorphous powder.

Analysis (referring to the anhydrous compound) H4.59 N7.50 Bd21.06

H4.65

9.86 g (93% of the value

040.21 040.16

No, 08

C · 3. X L. Ll X «3.0. Ui

N7.47

Gd 21, OO

Ma.3.1 /

EXAMPLE 23

a) 2,3-Epoxy-1- [4- (ethoxycarbonyl) -phenoxy] -propane

In analogy to example 6b), use ethyl 4-hydroxy-phenyl carboxylate in place of the compound of example 6a).

Yields 73% of the theoretical value of a colorless oil.

Analysis (referring to the anhydrous compound)?

C64.85 H6.35 calculated

C64.78 Hó, 43

b) Q- [2-Hydroxy-3- (4- (carboxy) -phenoxy) -propyl] -1, 4,7-tris (carboxymethyl) -1,4,7,10-tetraasacyclododecane

Dissolve 10 g (28.87 mmol) of

1,4,7-triscarboxymethyl-1, 4,7,10-tetraazacyclododecane (D03A) and 12.98 g (51, 96 mmol) of 2,3-epoxy i -1 C 4- (2-ethoxyl) carbon i 1) —phenoxy3-propane in 80 ml of dioxane / 60 ml of water, and adjust to pH 13 with 6N KOH »Stir for 12 hours at room temperature, then boil under reflux for 2 hours. Adjust to pH 7 with 5M HCl and evaporate to dryness in vacuo »Shake the residue with 200 ml of ethanol / 50 ml of chloroform at 60 ° C» Filter the precipitated potassium chloride and evaporate the filtrate in vacuo »Purify the residue on a reverse phase column (RP-18, wash with water, then elute with tetrahydro-furan / water = 2sD »Evaporate the main fractions in a vacuum»

Yields 8.43 g (54% of theory) of a glazed compound »

Analysis (referring to the anhydrous compound) s 053.32 H6.71 N10.36 calculated

053.29 H6.81 NIC, 31

c) Gadolinium complex of lQ- [2-Hydroxy-3- (4- (carboxy) -phenoxy) -propyl] -1, 4,7-tris (carboxymethyl 1) -1,4,7, lú-tetraaaaeiclododecane ( sodium salt)

Dissolve 8.1 g (14.98 mmol) of the compound of example 23b) in 70 ml of deionized water and add 2.72 g (7.49 mmol) of gadolinium oxide »Heat 3 hours at 90 ° 0» Stir solution cooled for 1 hour at high temperature with 10 m1 der esi in the first and acidic ρ ermut ionic (AMES 252c) »Filter the resin» Adjust the filtrate to pH

7.2 with 2N NaOH and lyophilize »

Yields 9.99 g (93% of theoretical value) of an amorphous, colorless powder »

EXAMPLE 24

a) 2,3-Epâxi-1- [4- (ethoxycarbonyl) -benzyloxy] -propane

In analogy with example 6b) ut i 1 i z ai ·· 4-h i ci r ox i --F en i 1 acet at d e et i 1 o in 1 ug ar d o omp o t of example 6a5 »

Yields 53% of the tory value of an inco1or oil «

Analysis (referring to the anhydrous compound);

066.09 H6, calculated S3

C66.16

ΓίΟ π i O ta) 10- [2-Hydroxy-3- (4- (2-carboxymethyl) -phenoxy) -propyl] -1, 4,7-tris (carboxymethyl) -1,4,7, 10-tetraasacyclododecane

Dissolve lu g (28.8 / mmol) of

1,4,7-triscarboxymethyl1-1,4,7,10-tetraazacyclododecane C = D03A) and

12.99 g (51.96 mmol) of 2,3-epoxy-1-C4- (2-ethoxy carbonyl 1) -benzyloxy3-propane in 80 ml of dioxane / 60 ml of water, and adjust to pH 13 with KOH 6N »Stir for 12 hours at room temperature, then boil under reflux for 2 hours» Adjust to pH 7 with 5N HCl and evaporate to dryness in vacuo »Stir the residue with 200 ml. d ethanol / 50 ml. chloroform at 60 ° C »Filter the precipitated potassium chloride and evaporate the filtrate in vacuo» Purify the residue on a reverse phase column (RP-18, wash with water, then elute with tetrahydro-furan / water = 2sD »Evaporate the main fractions in a vacuum »

Yields 8.17 g theoretical) of a glazed compound »

Analysis (referring to the anhydrous compound) s 054.14 H6.91 N10.10 calculated

054.09 H6.98 N10.02 (hi% of the value

Gadolinium complex of

10- [2-Hydroxy-3- (4- (2-earboxymethyl) -phenoxy) -propyl] -1,4 _f 7-tria (carboxymethyl) -1 _f 4 _f 7 _f iO-tetraaxaeielododeeano (sodium salt)

Dissolve · 7.9 g ¢ 14.24 mmol) of the compound of Example 24b) in 80 ml of deionized water and add 2.58 g (7.12 mmol) of the gadolinium oxide »Heat 3 hours at 90 ° C» Stir the solution cooled for 1 hour at room temperature with 10 ml of slightly acidic CAMB 252c ion exchange resin) »Filter the resin» Adjust the filtrate to pH 7.2 with 2N IMaOH and lyophilize »

Yields 9.58 g theoretical) of an amorphous, colorless powder »

Analysis (referring to the anhydrous compound)?

C41.09 H4.69 • v? U / I? Λ W “.“ '.

gu? 4. c .. ^: u a. .5. 3 (92% of the value

Gd21.52

Na3.15 Na3 »21 calculated

EXAMPLE 25

Bis-palmitinic ester of the gadolinium complex of 10- (1-hydroxy-methyl-2,3-dihydroxypropyl) -1,4,? - tris (carboxymethyl) 1,4,7,10 — tetraa ^ acyclododecane

Dissolve 5 g (8.28 mmol) of the gadolinium complex of 10- (1-hydroxymethyl1-2,3 ~ dih id ró xi ρ rop i1) -1,4,7-tr is (with boxi met i1) - 1,4,7,10 tetraazacyclododecane (see European Patent NS »912500 (31.6) in

100 ml of dimethyl ~ formamide add 4.04 g (40 mmol) of triethylamine »Add dropwise over 1 minute, 6.8d g (24.83 mmol) of palmitinic acid chloride» Stir for 2

Evaporate the dry solution

R P — 18 (f a s ε days at room temperature »vacuum, and chromatograph the residue on reverse / gradient water / acetonitrile eluents)»

Yield? after evaporating the main fractions, 7.25 g (81% of theoretical value) of a m a c p o s t o c e r o s are obtained »

Analysis (for anhydrous compound) s

1M5 η 18 bids 14 η 54 falls cuil ado

Òl

HS, 48 H8 »30

NS

Sdl i od et d e et i 1 of 10-undecene-al. of

EXAMPLE 25

a) 3-Hydroxy-tridec (12) and n

To a solution

-magnesium (prepared from 2.92 g (120 mmol) of magnesium and IS, 7 g <120 mmol) of ethyl iodide in 50 ml of ether) add a solution of 16.83 dropwise at 0 ° C g (100 mmo].) in 30 ml of ether during hOP & S carefully qot <

room temperature. Add 100 ml of water, and adjust the aqueous phase to pH 2 with 10% HCl. Separate the organic phase, and extract the aqueous phase 2x with 40 ml of ether respectively. Dry the combined organic phases over magnesium sulphate and evaporate in a vacuum. Chromatograph the remaining oil on top (eluent: hexane / ethyl acetate = 20%).

Yield? 16.86 g (85% of theoretical value) of an internal oil »

Analysis (referring to the anhydrous compound)?

C78.72 Η13.21 ca1c u1ad o

878.90 H13.12

b) S-Bensyloxy-tridee (12) and no 16 g k80.6 (mmol) of the compound of example 26a) in 200 ml of dimethylformamide, add 2.52 g (104.87 mmol) of sodium hydride and stir for 2 hours at 50 ° C. Cool in an ice bath at 0 ° C and add 17.94 g (104, '87 mmol) of benzyl bromide. Then stir overnight at room temperature. Add SOO ml of water and extract the solution 2x with 200 ml of hexane. Dry the combined organic phases over magnesium sulphate and evaporate in vacuo.

Yields 23.03 g (99% of theory) of a colorless oil.

Analysis (referring to the anhydrous compound)?

883.27 Hl1.18 calculated

883.15 Hl 1.25

c) 1,2-Epâxi-11-ben2Loxy-tridecane Di ssolver

14, í

31.3 mmol) dc

compound of example 26b) in 100 ml of chloroform. At 0 ° C add 11 ₅ d 1 g (6 6.7 mmo 13 deacidom— c 1 oro —per ô xi · b θ η z ΰ ic o. To g 11 air for 24 hours at room temperature. Filter the precipitate, and wash the filtrate several times with concentrated sodium carbonate solution »Dry the organic phase over magnesium sulphate and evaporate in vacuo» Chromatograph the residue on top of it (eluents hexane / ethyl acetate 15s 1) »

Renewals i 2.5 g (80% of theoretical value) of a colorless oil »

Analysis (referring to the anhydrous compound)? G7S, 90 Kl0.50 calculated

C7S, 77 Hl0.65

d) 10- (2-Hydroxy-11-bensyloxy-tride) 1) -1,4,7-tris (carboxymethyl) - !, 4,7, 10-tetraazacyclododecane

In analogy to example 4a) the compound of example 26c) was used instead of the epoxide used in example 4a) »

Yield?

of the theoretical value of a uumpQ

Análi se is glazed, (referring to

C62

L. | O p 1 t> * ~ u tj O · J.

h i g rqsc op i co. anhydrous compound)? N8.61 Calculated

NS, 75

e) Gadolinium complex of l- (2-Hydroxy-11-benzyloxy-tridee 1) -1,4,7-tris (carboxymethyl 1) -1,4,7,10-tetraazacyclododecane

In analogy to example 4b)

uti1i z ou o p a a complexation the compound of example 26d) in place of compound c example 4a 3 » Income § 96% d the theoretical value of a colorless powder, love f o » A n â 1 i s e (r ε f s r e n t e to the compound anhydrous)§ L- · vJ y í V 10 rj UÍ Z Nò, 96 C 3. 1U. 1 3. d Q Ct> U, 60 Hò, 9 & Nò, 84

EXAMPLE 2?

a) 1 - [(4-Benzyloxy) -phenoxy] -undec (10) ene

Stir · overnight at 70 ° C 32.43g (lou mmol) of the p-toluene ether of the W-undecenoi, 20.03 g (100 mmol5 of 4-benzyloxy-phenol and 5.61 g (100 mmol) of finely pulverized sodium hydroxide, cool, add 500 ml of IN NaOH and separate the organic phase Extract the aqueous phase ix with 100 ml of toluene, dry the combined organic phases over magnesium sulphate and evaporate in a vacuum. Recrystallize the residue with a little hot methanol.

Yields 26.44 g (75% of the theoretical value of colorless plates.

Analysis (referring to the anhydrous compound)?

881.77 H9.15 calculated

881

b) 1 _f 2-ΕράκΙ-11 - [(4-benzyloxy) -phenoxy] -undecane

In analogy to example 26c) the compound of example 27a) was used for spoxidation instead of the compound of example 26b).

Yields 87% of the theoretical value of a crystalline compound (with methanol).

Analysis (referring to the anhydrous compound)?

calculated

Γ '··? »

L .. · i O tj jIm aU

878.05

HS, 87

863.84

c) 10- [2-Hydroxy-11- (4-benzyloxy-phenoxy) -undeci1] -1, 4,7-triscarboxymethyl 1-1,4,7,10-tetraazacyclododecane

In analogy to example 4a) the compound of example 27b) was used in place of the epoxide used in example 4a).

Yields 69% of the theoretical value of a glazed compound.

Analysis (referring to the anhydrous compound)!

M7.84 c a1c uIad

N7 ,, 6 O

H8.31

d) Gadolinium complex of 10- [2-Hydroxy-11- (4-benzyloxy-tenáxi) -undeeyl] -1,4,7-trisearboximati1-1,4,7,10-tetraasacie1ododeoano

In analogy with example 4b) the compound of example 27c) was used for complexation instead of the compound of example 4a) «

Yield: 98% of the theoretical value of a colorless, crystalline powder.

Analysis (for anhydrous compound) §

C52.51 146.33 Node, 45 Gd 18.09 calculated

C52,32 Hó, 45 N6,28 Gd 17,91

EXAMPLE 28

10- [2-Hydroxy-ll- (4-hydroxy-phenoxy) -undeeyl] -1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododeean

In analogy to example 7, the compound of example 27d) was hydrogenated „

Yields 97% of the theoretical value of a compound v i d r ad o.

Analysis (referring to the anhydrous compound):

C47.80 146.34 N7.19 Gd20.19 calculated

C47, H6.50 N7.02 Gd20.03

Ex p em ents for Galenic Forms

1) Dissolve 372.42 g (0.5 mol) of the complex salt obtained in example 21c) in 500 ml of water pro injectione (p.i.), heating slightly. After adding 1.2 g of tromethamine, make up the neutral solution to 1000 ml with water p.i .. Ultrafiltrate the solution and pour into vials. After hot sterilization it is ready for parenteral application.

2) Mix 128 g (0.19 mol) of the complex of example 14b) very well with 120 g of sucrose and 5 g of polyoxyethylene polyoxypropylene, adding 10 mg of raspberry flavoring »□ powder thus obtained is for oral administration»

i a.-Plasma Riaxiity) of some selected examples

Example NS. T _x -Important relaxation „s)“ '· * 1b 7.30 2b 7 g 2? 3b 7.16 4b 24.47 5 c 12.18 6d 24.16 7 9.91 Sb 5.76 llb 8.66 12b 10.23 13b 8.70 14b 7.25 21c 7.28 23c 7.04 Magnevist® 4.90 Dotarem® 4.30

«) Ti-relaxivity was measured with a CMinispec F'G20 NMR spectrometer at 20 Mhz (= 0.47 T) and 39 ^Q C in human plasma

Example for an in vivo NMR diagnosis

For nuclear magnetic resonance tomography, the experimental animals (rat, Wistar Han d ¹ - with Novikoff's hepatoma in the liver) were narcotized (Rompun® * · Ketavet®), and a catheter was applied to the tail vein. for administration of the contrast medium »The test was carried out in an experimental apparatus MRl by General • Electric (power 2 7sla)« The records were made with □□

a balanced spin and echo sequence for TiíTFi ™ 400 m sec, TE = 20 m sec, 8 medium, 3 mm layer thickness, axial cuts). Figure 1 represents the liver with the tumor before administration of the contrast medium »The tumor has a density more or less similar to that of the parenchyma (isodense) and cannot be delimited from that» 1 minute after i »v administration »Of the compound of example 14b) (0.1 mmol Gd / kg), the liver has an increased signal strength, while the tumor signal strength (top right) has not changed, so they can be distinguished very well from each other (Figure 2) »Also, 30 minutes after administration (Figure 3), the contrast between the liver and the tumor is completely maintained» This means that, unlike preparations com a ci a1i z ad as Magnev i si® and Dot arem®, this component is accumulated in the liver, and in this way and in comparison with those, with the same dose it produces in the first place a better contrast between the liver parenchyma and the tumor and also other pathological structures), and sm second place this contrast lasts longer »This last point is advantageous, as it provides ..... if you give a longer period of time for a successful diagnosis»

PICTURE'S DESCRIPTION

OJ

Axial image of a rat at the liver level, without contrast medium »The tumor growing in the upper right quadrant of the liver is not visible.

Sectional plane identical to that of Figure 1 »The image was obtained 1 minute after the administration of the compound of example 14b)» The liver now has a greater intensity of the signal, making the delimitation of the tumor easy »

Sectional plane identical to that of Figure s 2. The image was obtained 30 minutes after the administration of the compound of example 14b). Virtually the same contrast is observed between the liver and the tumor as immediately after administration of the contrast medium.

Claims (2)

R E I N V I N D I C A g E 8 Process for the preparation of tetraazacyclododecane compounds of the general formula I, ^E vv ^and / \ (I) \ , / v i mp na gual E represents a radical -CH (R ¹ ) ~ COs »Y with Y = a hydrogen atom and / or a metal ion equivalent of an element with the order numbers 21-29, 31, 32, 37-39, 42 -44, 47, 49 or 57-83, and R ¹ = a hydrogen atom, an alkyl group with 83.-8-50 optionally substituted with 1 to 6 hydroxy groups, straight or branched chain, an aryl group with Ε _ώ -Ε _1ο or air-alkyl with Cv — 8305 0. represents a —CHCR '> ~ CHÍ0H) R radical, with R = an alkyl group with 0 _± -0- _ΐΟ straight or branched chain, or ar-alkyl with C ·? ..... ~ C.- " _O , containing 1 to 10 atoms with oxygen and eventually substituted with 1 to 6 hydroxy or OCOR ⁵³ groups, where R ^s represents a hydrogen atom or a straight or branched C 1 -C 6 alkyl radical, aryl with C ^ -Cio or ar-alkyl with CyC ^ o, which may eventually have 1 to 2 groups ..... OCO, 1 to 2 cyclohexane and / or cyclohexyl radicals (which in turn can be replaced with ia 3 groups (CH _K ) _K COOR ^H where K - 0-10), possibly 1 to 5 alkoxy groups with Ca. · -Cy, aryloxy with Coke. o or aralkoxy with Ct-Cio, possibly a radical -WR ^ -COR® or -COíMR ^ R®, where R ^{: s} have the definitions indicated by R®, and / or 1 to 2 COsR ⁵² radicals; and the aryl radicals optionally present in the chain may be substituted with 1 to 3 alkyl radicals with him C; _{LC: are} straight chain or branched, aryl of C _a -C _ie air or alkyl having _{CrC; s5O} which represent optionally 1 to 5 oxygen atoms, 1 to 3 hydroxy groups, 1 to 5 alkoxy groups with Οχ-Ο ·, .- and / or 1 to 3 groups (CH ₃ ) _K COOR ^ j, or with ia 3 radicals F, Cl Br, -OH, us-, _h NH -, NCS, CO _s R ^s, Cl NHC0CH _s, NHCOCHssBr-, NHCOCH -p _and R R ^? represents a hydrogen atom or R, and if FF represents a hydrogen atom s ds be in the presence of a Ξ-oxa-alkyl chain with Cx-C-so, it must be replaced with at least one of the radicals described above, in addition to a methoxy or ethoxy tsrmi nal group possibly presentρ or represents a second tetraazacyclododecane molecule linked via a bisCShhydroxy chain) ..... alkylene “CHs-CH-K-CH-CHsa- where K represents an alkylene chain OH with _a C.-C * containing 1 to 6 oxygen atoms, optionally 1 to 2 grub TA 1 snzi XI, phenylene, phenyl Xie η 1 and / or -N- and η 1 and η χ ô ODI χ i, and evsntually replaced with 1 to 6 hydroxy groups, 1 to ô h ^c ? hydroxyalkyl groups with C ₄ -C _tfa and / or 1 to 8 alkoxy groups with C _{1 -C-} , · 'or air-alkoxy§ or their salts with inorganic and / or organic bases, amino acids or amino acid amidesg characterized because compounds of the general formula II are reacted in which Ξ 'represents the radical indicated by E, in which any hydroxy groups are eventually protected, with an educate of the general formula III or IV (IV). where! <'represents the radicals indicated for K, in which possible hydroxy groups are eventually protected, • η: ^ίΛ and R ^to have definitions indicated for R ^? and R, but do not contain any NH _a , NCS, NHCOCH ^ Cl or iMHCOCH®Br groups, and where any carboxyl groups are eventually protected, in water or water-miscible solvents, such as p »e = acetonitrile, DMF, DMA, ethanol, methanol, dioxane, THF, DMSO, DME or mixtures thereof, at temperatures of 0 ° --170 * 0 preferably at 20 ⁰ ~ 100 ⁰ C for 12 to 48 hours, preferably for 12 to 24 hours, adding inorganic and / or organic bases such as potassium, sodium, lithium, calcium, barium, magnesium hydroxide, sodium potassium carbonate, triethylamine, tripropylamine, tributylamine, pyridine, DMAP, Rsí11sx ' ^{: r:} Triton Β ^{ςΡ !?} if they do not represent any protective groups still present, react with the complexing agents thus obtained (hydrogen atoms) with at least one metal oxide or metallic salt of an element with order numbers 21-29, 31 , 32, 37-39, 42-44, 47, 49 or 57-83, then - if desired - if the acidic hydrogen atoms present are replaced by cations of organic and / or inorganic bases, amino acids or amino acids amino acids, starting, if the desired final compounds must contain the groups NH _a , NCS, NHCOCH ^ Cl, NHCOCH ^ Br- or CQN ^, of educts of the general formula III which instead of these groups groups N0 _H - or CO _K R ^a -, then transforming the latter groups mentioned in the functional groups mentioned above and desired, and this transformation can be carried out before or after complexing agents and subsequent replacement of acidic hydrogen atoms gifts with the metal ions respectively desired » Process according to the preceding claim, characterized in that compounds of the general formula I are obtained in which Y represents hydrogen atoms » Process according to claim 1, characterized in that compounds of the general formula I are obtained in which at least two of the Y substituents represent metal ion equivalents of an element with the order numbers 21-29, 42, 44, 57-83, or at least one radionuclide of an element with the order numbers 21, 26, 27, 29, 31, 32, 37-39, 43, 47, 49, 62-64, 67, 70, 71, 75, 77, 79 and 83 »rei vi ntii cation general formula Process 1, with the ad ο ρ or 1 in which R ¹ represents according to whether to obtain a hydrogen atom a ^Γ - · Ι s claim general formula Process according to 1, characterized by obtaining compounds of the I in which R ¹ represents a hydrogen atom » - 6® Process for the preparation of pharmaceutical compositions containing as active ingredients at least one physiologically tolerable compound of the general formula I, when prepared according to any of the preceding claims, characterized by the incorporation of these complex compounds dissolved or suspended in water, saline solution physiological or protein solution, possibly together with the usual galenic additives, in a formulation. suitable for enteral or parenteral administration » V The applicant claims the priority of the German application submitted on 8 November 1990, under the